Preparation of 17alpha-propadienyl steroids

ABSTRACT

Disclosed is a process for the preparation of 17a-propadienyl steroids of the estrogen, estrane, and androstane series which contain optional substitution at other positions of the nucleus. This process involves treating a corresponding 3-(halopropynyl) steroid with a metal, metal couple, or metal salt reagent in organic reaction media and in the presence of a proton donor. The product 17a-propadienyl steroids of the 6,6-difluoroandrostane and 19-norandrostane series, optionally substituted at the C-3, C-17, and C-18 positions, are new compounds. The 17a-propadienyl products are useful as estrogenic, anti-androgenic, and progestational agents.

United States Patent 91 Crabbe et al.

[ 1 Apr. 17, 1973 [5 PREPARATION OF 17ALPHA- PROPADIENYL STEROIDS [75]Inventors: Pierre Crabbe, Mexico, Mexico;

John H. Fried, Palo Alto, Calif.

[73] Assignee: Syntex Panama [22] Filed: July 27, 1971 [21] Appl. N0.:166,628

Corporation, Panama,

Related U.S. Application Data [52] US. Cl...260/397.4, 260/239.55 R,260/397.45, 260/3975, 260/3973, 424/243 [5 l Int. Cl. ..C07c 169/08,CO7c 169/20 Primary ExaminerElbert L. Roberts Att0rneyEvelyn K. MerkerABSTRACT Disclosed is a process for the preparation of 17apropadienylsteroids of the estrogen, estrane, and androstane series which containoptional substitution at other positions of the nucleus. This processinvolves treating a corresponding 3-(halopropynyl) steroid with a metal,metal couple, or metal salt reagent in organic reaction media and in thepresence of a proton donor. The product l7a-propadienyl steroids of the6,6- difluoroandrostane and l9-norandrostane series, optionallysubstituted at the C-3, C-l7, and C-l8 positions, are new compounds. Thel7a-propadienyl products are useful as estrogenic, anti-androgenic, andprogestational agents.

24 Claims, No Drawings PREPARATION OF l7ALPHA-PROPADIENYL STEROIDS Thisis a continuation-in-part of application Ser. No. l48,l73,.filed May 28,1971 now abandoned which is a continuation-in-part of application Ser.No. 817,562, filed Apr. 18, 1969 now abandoned.

The present invention relates to a novel process which is useful in thepreparation of useful steroidal compounds. Specifically, this inventionis directed to a process useful in preparing steroidal l7a-allenes.

Certain of the steroid compounds which have a 17aethylenicallyunsaturated side chain, specifically a I70:- propadienyl (allene)grouping, are novel, particularly those l7a-propadienyl steroids of the6,6-difluoroandrostane and l9-norandrostane series represented by theFormula (I).

Other l7a-propadienyl steroids have been described. For example, US.Pat. Nos. 3,392,]65 and 3,392,l66 disclose, inter alia, thosederivatives of the estrogen, estr-4-ene, estr-5( lO)-ene andandrost-4-ene series as represented by Formulas (II), (III), and (IV).

(III) om a "Ill-4 ml:

Other useful l7a-propadienyl steroids can be represented by thefollowing formulas:

1 l CHzi....CH=C=CHz In the above and succeeding I formulas, R ishydrogen or lower alkyl of from 1 to 3 carbon atoms,

in which R is hydrogen, tetrahydrofuran-Z-yl, tetrahydropyran-2-yl, or acarboxylic acyl group containing less than 12 carbon atoms; R ishydrogen or methyl; R is hydrogen, lower alkyl of from I to 8 carbonatoms, inclusive, cycloalkyl, tetrahydrofuran-Z-yl,tetrahydropyran-Z-yl, or a carboxylic acyl group containing less than 12carbon atoms; and Z is a carboncarbon single bond or a carbon-carbondouble bond.

The l7a-propadienyl derivatives in the estral,3,5( l0)-triene series(Formula II) possess estrogenic and antiandrogenic activity and areuseful in the manner such agents are customarily used for the treatmentof conditions responsive to estrogenic'and antiandrogenic agents, suchas the control and regulation'of fertility and the treatment of acne,benig'n'prostate hypertrophy, and hirsutism in females. The17apropadienyl derivatives in the 6,6-difluoroandrostane,6,6-difluoro-l9-norandrostane, estr-5( lO)-ene, estr-4- ene,androst-.4-ene, estra-4,9( l0)-diene, estra-4,9( l0), 1 l-triene, andestra-5( l0),9(l l )-diene series (Formulas I, III, IV, V, and VI)demonstrate progestational,

pituitary inhibiting, and anti-fertility activity and areuseful in themanner corresponding to such activity such as in the treatment ofvarious menstrual disorders and in the control and regulation offertility.

The novel process of the present invention comprises reacting a l7a-(3-halopropynyl) steroid compound with a reagent selected-from metalshaving an oxidation potential between +2.37 to +0.74 volts inclusive(meabodiments, the present invention is particularly useful for thepreparation of the l7a-propadienyl steroids of the estrogen, estrane,and androstane series depicted above in Formulas (I), (II), (III), (IV),(V), and (V1).

The metal, metal salt, or zinc-copper couple reagent is employed in atleast chemical equivalent amounts with the steroid starting material.Amounts in excess of this, upwards of a 20 to 50 molar excess, canconveniently be employed. Preferred embodiments involve the use of from1.5 moles of 20 moles of metal or metal salt reagent per mole ofstarting steroid.

The reaction is conducted in the presence of organic liquid reactionmedium. Suitable media include the customary organic solvents, forexample, lower aliphatic alcohols 'such as methanol, t-butanol,npropanol, and the like; ethers such as dimethyl ether, dioxane, methylpropyl ether, tetrahydrofuran, and the like; lower aliphatic ketonessuch as acetone, methyl ethyl ketone, and the like; saturated aliphatichydrocarbons such as pentane, hexane, octane, and the like; aromatichydrocarbons such as benzene, toluene, mesitylene, and the like; andcarboxylic acids containing less than 12 carbon atoms such as acetic,propionic, trifluoroacetic and the like.

The reaction is conducted in the presence of i a proton donor. Suitableproton donors include lower aliphatic alcohols such as methanol,ethanol, propanol, and butanol; carboxylic acids such as acetic,propionic, butyric, and hexanoic', and water; or mixtures thereof. Theproton donor is present in amounts approximately stoichiometricallyequivalent to the amount of metal or metal salt reagent employed.

When employing a lower aliphatic alcohol or carboxylic acid as liquidreaction media, it can also serve as proton donor. Mixtures of thevarious proton donors or mixtures of proton donors and other liquidreaction media or aqueous mixtures of water miscible liquid reactionmedia can also be satisfactorily employed. Suitable mixtures includeacetone-water, dioxanewater, benzene-n-propanol, and toluene-aceticacid. When carrying out the reaction with metals having an oxidationpotential higher than about +1.5 volts the organic liquid reactionmedium employed is preferably free of active hydrogen atoms. Propermedia include the aromatic solvents such as benzene and xylene, and theethers such as t-butyl ether, glyme, dioxane, or tetrahydrofuran.Similarly, when employing metals having an oxidation potential lowerthan about +1.5 volts, such as manganese or zinc, the organic liquidreaction medium employed is preferably a lower aliphatic alcohol such asmethanol, ethanol, and isopropanol or liquid carboxylic acids containingless than 12 carbon atoms such as acetic, butyric and hexanoic acids. Ifthe reagent employed is a metal salt, which generates a cation ofadequate oxidation potential, the reaction is preferably conducted in apolar organic liquid reaction medium which is inert to such salts. Suchinclude, for example, the lower aliphatic ketones, for example, acetoneand pentanone and the lower aliphatic alcohols including methanol andethanol. When the former mentioned ketones are used, the proton donor ispreferably provided by water and acetic acid.

The reaction is conducted at a temperature ranging from about 20C. toabout 120C. and preferably at the boiling point of the reaction mixtureand under reflux. The reaction is continued for a period of timesufficient to complete the reaction ranging from about 2 hours to about48 hours. Longer or shorter periods may be employed depending uponthe-choice of reaction temperature and reactants employed. In apreferred procedure, the starting steroid compound, dispersed in anorganic liquid reaction medium and proton donor, if necessary, istreated with the metal or metal salt reagent on at least a mole per molebasis. The resulting reaction mixture is then heated with stirring for asustained period of time. Upon completion of the reaction, therespective product is separated and recovered from the reaction mixturevia conventional techniques. Included in such conventional techniquesare filtration, decantation, evaporation, chromatography,recrystallization,

tion which contain a l7a-(3-halopropynyl) grouping are prepared from thecorresponding l7a-(3-hydroxypropynyl) compounds. Such conversion isaccomplished in the bromo and chloro series by treatment of the hydroxycompound with thionyl bromide or phosphorous pentabromide or withthionyl chloride or phosphorous pentachloride in the presence of atertiary amine base such as the tertiary alkyl amines, pyridine,lutidine, and so forth. The reaction is carried out'in any convenientorder or fashion at temperatures of from about 0 to about 20C. andconveniently, in organic liquid reaction medium, such as ether, benzene,and the like. See pp. 48+49 hereof for preparation of the iodocompounds. 0

Alternatively, the bromo and chloro derivatives can be prepared bytreating the hydroxy compound with tr'iphenylphosphine and carbontetrabromide or carbon tetrachloride in organic reaction medium, such asdimethylforrnamide and dioxane, at about C. for a few minutes followedby the usual recovery procedures.

In the fluoro series, the hydroxy compound is treated with a hydrocarbonsulfonyl fluoride includingbenzyl sulfonyl fluoride, tosyl fluoride andmesyl fluoride. This process also-preferably employs an inerthydrocarbon solvent such as hexane, heptane, benzene, toluene or anesterified or etherified alcohol such as dimethoxyglycol. Other suitablesolvents are chloroform and nitromethane. The reaction is carried out attempera.- tures of from 0C. to about C. for from I to 8 hours. 0

Alternatively, the 3-fluoropropynyl compounds are prepared by treatingthe 3-hydroxypropynyl compounds with l-diethylarninol l ,2-trifluoro-2-chloroethane in methylene chloride, acetonitrile, diethyl ether,dioxane, tetrahydrofuran, and the like, in the method known per se. seeU.S. Pat. No. 3,444,188, for example.

The l7a-(3-hydroxypropynyl) steroid compound from which the3-halopropynyl derivatives are prepared are, in turn, prepared viaseveral methods. In one such method, Grignard reagent is prepared upontreatment of the product of the reaction of propargyl alcohol anddihydropyran, 3-(tetrahydropyran-2'-yloxypropyne), with magnesium andethyl bromide in the method known per se. This reagent is then reactedwith a l7-oxo steroid. In this manner, the corresponding 1 7a-(3-tetrahydropyran-2'-yloxpropynyl) derivative is prepared. Thereafter,the thus formed derivative is conventionally hydrolyzed such as with-amineral or organic acid to hydrolyze the tetrahydropyran-2'-yloxy groupforming the hydroxyl.

steroidal In another method for the preparation of the 3-hydroxypropynyl compounds hereof, which method is particularly useful inthe estrogen series, a l7-oxo starting compound is ethynylated via themethod known per se, that is, through treatment with potassium acetylideto give the l7a-ethynyl-l7B-hydroxy derivative. Thereafter, thel7B-hydroxy group is preferably protected before further reaction, suchas by forming the tetrahydropyran-2'-yloxy or tetrahydrofuran-2-yloxyether thereof. In such further reaction, the ethynyl group is elaboratedas respect the addition of the hydroxymethyl group as a replacement forthe acidic hydrogen. This is accomplished by forming the ethynyl lithiumsalt (by treating the ethynyl derivative at room temperature with anequivalent amount of an ether solution of methyl, butyl, orphenyllithium) and treating this with an equivalent or slight excessamount of paraformaldehyde at gentle reflux in ether followed byhydrolysis in accordance with the procedures described by Schaap et al.in Rec. Trav. Chim. 84, 1200 1965) as well as the references citedtherein.

The procedures for preparing the starting 3- halopropynyl steroidshereof are more completely described in, for example, U.S. Pat. No.3,029,261.

ln the preparation of the starting l7a-(3-halopropynyl) derivatives inthe 6,6-difluoroandrostane and 19- norandrostane series, the foregoingpreparations can be practiced upon the corresponding6,6-difluoroandrost-4-ene-3 l 7-diones and6,6-difluoro-19-norandrost-4-ene-3,l7-diones and the l8-alkylderivatives thereof. In practice, the 6,6-difluoro grouping isintroduced into the precursor androst-4-ene-3,l 7-diones andl9-norandrost-4-ene-3,l7-diones or l8-alkyl derivatives thereof. Onemethod by which this is done is described in U.S. Pat. No. 3,219,673.This method involves treating a 3-acyloxy-5-fluoro-6-keto steroid (whichare known or can be prepared as described in the cited patent and itsreferences) with sulfur tetrafluoride to prepare the corresponding3-acyloxy- 5,6,6-trifluoro steroid which is hydrolyzed to the 3-hydroxy-5,6,6-trifluoro compound. The latter compound is oxidized to thecorresponding 3-keto-5,6,6- trifluoro derivative which is then treatedwith a dehydrofluorinating agent such as alumina to provide the 3-keto-A-6,6-difluoro compound.

Another method by which these 6,6-difluoro precursor steroids areprepared involves twice consecutively forming an enol ether and treatingthis with perchloryl fluoride. Thus, the startingandrost-4-ene-3,l7-dione is converted to its enol ether and it istreated with perchloryl fluoride to form the 3-keto-A -6-fluoroderivative. The same procedure is followed with this compound to formthe 3-keto-A -6,6-difluoro products. The enol ether formation andfluorination treatment are each conventional reactions in the steroidart.

The starting l7a-(3-substituted propynyl) compounds in the A'"-estradiene, A ""-estradiene, and A-""-estratriene series are preparedfrom the corresponding l7-oxo compounds as described above. The A""-estratrien-l7-one compounds are known and can be prepared by treatinga 3-keto-A steroid with bromide in pyridine solution to form thecorresponding 3-keto-A -diene, ketalizing the resultant diene to thecorresponding 3-ketal-A "-diene, epoxidizing this ketal diene with aperoxy acid, and treating the epoxidized product with strong acid.Alternatively, a 3-keto-A- is treated with hydrogen chloride in methanolat room temperature to obtain the corresponding 3,3-dimethoxy-A compoundwhich is hydrolyzed to give the 3-keto-A compound. This compound is thenconverted to the 3-keto- N and thence to the 3-keto-A""" compounds asdescribed above. See Steroids 8:1, p. 87 (July 1966) and U.S. Pat. Nos.3,282,785 and 3,461,118, the subject matter of which is herebyincorporated by reference. The l7-oxo compounds in the A A and A seriesare reduced such as with lithium tri-t-butoxy aluminum hydride, to formthe 3,l7-diol. This is acylated and the 3-acylate-l7-ol separated bychromatography. The 17-alcohol is then oxidized such as with chromicacid to provide the 17- one compound which is elaborated as describedabove.

Alternatively, the 3-keto-17B-ol compound can be protected by formationof the 3,3-ketal followed by oxidation of the 175-01.

In the preferred embodiments, the desired noninterfering elaborativegroupings at the other optional sites of the molecule are introducedprior to the novel, principal reaction hereof. Protection is preferablyprovided for those groups which may compete or interfere with theprincipal reaction hereof or with the processes preparative tto theprincipal reaction hereof. Examples of such protection include formingthe ketal or enol ethers or the 3-oxo function which can be restoredlater in the synthetic sequence.

In the estrogen series, treatment of, for example, thel7a-ethynyl-3,l7/3-diol derivative with an appropriate carboxylic acidanhydride, such as acetic anhydride, in pyridine yields the3-acyloxy-l7B-hydroxy derivative selectively. Use of an acid anhydridein the presence of the corresponding acid and an acid catalyst such asptoluenesulfonic acid yields the 3,17B-diacyloxy derivative. Thisdiester may then be selectively saponified as through the use ofmethanolic potassium bicarbonate to yield the corresponding3-hydroxy-l7/3-acyloxy derivative. Similarly, etherification may beperformed via the conventional procedures. Thus, treatment withdihydropyran in the presence of an acid catalyst such asp-toluenesulfonic acid, p-toluenesulfonyl chloride, dinitrobenzenesulfonic acid or the like, yields the correspondingtetrahydropyran-Z-yloxy derivative. Formation of themono-tetrahydropyranyl ether may be accomplished by selective protectionof other hydroxy groups as through ester formation, in the mannerdescribed above, with alkaline hydrolysis of such ester groups afterformation of the ether, if desired. Formation of 3-methoxy derivativesmay likewise be realized through the use of dimethylsulfate andpotassium hydroxide in the conventional manner.

Similar conventional esterification and etherification procedures can beemployed in the other series of starting compounds for the presentinvention. For example, in the preparation of the 3B,l7B-diacylatestarting materials for the process hereof, the 3,17-dioxo compound canbe reduced and acylated with about one chemical equivalent of acylatingagent. The product I mixture is then chromatographed to separate the 3B-acylate-l7B-ol compound. This derivative is then oxgroup at C- 1 7a, asdescribed'above, is then followed including the addition of theappropriate acylating agent before workup to form the3B,l7,B-diacylate-l7atetrahydropyranyloxypropynyl compound. Thiscompound is then converted to the corresponding halopropynyl derivative.

The 313, l7B-diethers can be conveniently formed by initially preparingthe 3B, l7B-diethers and then following this with the formaldehydemethod of preparing the l7a-hydroxypropynyl compounds, as describedabove.

If a mixed ester-ethercompound is desired, the monoether is prepared ina sequence similar to that used for preparing the mono-acylate.Thereafter, the described Grignard method is followed ending with anacylation before work-up. Alternatively, the monoacylate prepared asdescribed above, can be ethynylated at C-l7a and the C-17B hydroxyletherified. Thereafter, the described formaldehyde method is employedfor the preparation of the corresponding 17ahydroxypropynyl compound.

In the present specification and claims, the term carboxylic acyl groupand carboxylic acyloxy group denote acyl and acyloxy groups whichcontain less than 12 carbon atoms and which can be of a straight,branched, orcyclic chain structure. This structure can further besaturated, unsaturated or aromatic and optionally substituted byfunctional groups such as hydroxy, alkoxy containing up to carbon atoms,acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno and thelike. Representative esters thus include acetate, propionate, enanthate,benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, aminoacetate, B- chloropropionate, adamantoate,bicyclo[2.2.2] octanel -carboxylate, bicyclo[ 2.2.2 ]-oct-2-ene- 1-carboxylate, 4-methyl-bicyclo[2.2.2] oct-2-ene-l-carboxgroup which isrepresented above by R include, for

example from 3 to 8 carbon atoms. In the present specification andclaims,-the term 3-halopropynyl includes 3-bromopropynyl,3-chloropropynyl, 3-

iodopropynyl, and 3-fluoropropynyl, preferably 3- chloropropynyl.

The following preparations and examples serve to further illustrate themanner by which the present invention can be practiced. As such,however, they should not be construed as limitations upon the overallscope hereof.

PREPARATION l A solution is prepared by dispersing 29 grams of estr-4-ene-3,l7-dione in 600 ml. of dioxane at room temperature withstirring. Ethyl orthoformate (60 ml.) and 1.8 grams of p-toluenesulfonicacid hydrate are added to the resultant mixture. The addition isconducted portionwise, with stirring, and atroom temperature. After theaddition is complete, the resulting reaction mixture is allowed to standat room temperature for three and one half hours. After this time, theresulting solution is poured into two liters of ice water. After thishas been accomplished, the whole mixture is filtered to yield acrystalline material which is recrystallized from methylenechloridezmethanol containing a few drops of pyridine to obtain thedesired 3-ethoxyestra-3,5-dienl7-one product.

Proparagyl alcohol (42grams) is dispersed in 63 grams of2,3-dihydropyran with stirring. While continuing the stirring at roomtemperature, phosphorous oxychloride (500 mg.) is added portionwise tothe resultant solution. The reaction mixture rapidly becomes warm and iscooled intermitentiy in ice. After maintaining these conditions for 2hours and then allowing the temperature of the reaction mixture tostablize at room temperature, an aqueous solution of potassium hydroxideis added. The mxiture is then extracted with ether and the etherextracts distilled under gradually increasing temperatures and graduallydecreasing pressures to obtain the 3-tetrahydropyran- 2 yloxy-p'ropyneproduct.

Under anhydrous conditions, 3.2 g. of magnesium, l 1 ml. of ethylbromide, and 150 ml. of absolute ether are mixed together at roomtemperature. To the resulting solution is added, dropwise and at roomtemperature, 30 g. of the 3-tetrahydropyran-2'-yloxypropyne productobtained as described above. The temperature of the resulting mixture isheated to the boiling point and maintained under reflux conditions for 5minutes. After this time, the mixture is cooled to room temperature andmixed dropwise with a solution containing2l grams of3-ethoxyestra-3,5-dien-l7-one which is dispersed in 200 ml. oftetrahydrofuran. After this addition is complete, the reaction mixtureis stirred at room temperature for a period of 2 hours. The resultingsolution is cooled in an icebath and then mixed with ml. of aceticanhydride. This solution is then left at room temperature for 16 hours.After this, the mixture is poured into an ammonium chloridezice solutionand this is then extracted with ether, the ether extracts being driedand evaporated to a concentrated form. The concentrate ischromatographed to obtain a crystalline product which is crystallizedfrom ethyl acetate:hexane:petroleum ether. Recrystallization from thesame solvent mixtures obtains the desired l7a-(3- tetrahydropyran-2-yloxypropynyl l 7B-acetoxyestr-4- en-3-one product.

1 7a-( 3-Tetrahydropyran-2 -yloxypropynyl )--l 7 B-acetoxyester-4-en-3-one (18 g.) is dissolved in 750 ml. of methanol atroom temperature. Thereafter,'2( g. of oxalic acid is dispersed in 150ml. of water and. the resultant aqueous oxalic acid solution is added tothe steroid methanol solution at room temperature in a portionwisefashion. The resulting reaction mixture is left overnight at roomtemperature. The reaction mixture is then neutralized by the portionwiseaddition of sodium hydroxide and then the neutralized mixture isfiltered. The filtrate is concentrated in vacuumto a residue. Theresidue is extracted with an etherzmethylen'e chloride mixture toprovide a solution which is then dried over sodium sulfate. The driedsolution is evaporated to obtain a solid. The solid is chromatographedon a column of silica gel eluting with hexanezethyl acetate (lzl) toobtain a substance which is recrystallized from ethyl acetatezhexane toobtain the 1 7a-( 3-hydroxypropynyl l 7B-acetoxyestr-4-en-3 -one prodcutas a crystalline solid.

A mixture of 20 ml. of absolute pyridine, 8 ml. of freshly distilledthionyl chloride, and ml. of absolute tetrahydrofuran is prepared atroom temperature with stirring. 1 7a-( 3-I-Iydroxypropynyl l7B-acetoxyestr-4- en-3-one (3.4 g.) which is dissolved in 50 ml. ofanhydrous tetrahydrofuran is added to the resulting solution over a 25minute period at room temperature. After the addition is complete, thereaction mixture is stirred at room temperature for 35 minutes. Afterthis period of time, the mixture is poured into ice water and theresulting mixture is extracted with etherzmethylene chloride. Theextracts are washed with water and dried over sodium sulfate. The driedmaterial is evaporated to an oil. The oil is chromatographed on silicagel to obtain the desired 17a-(3-chloropropynyl)-l7B-acetoxyestr-4-en-3-one product.

In like manner, the foregoing procedures can be practiced on thecorresponding l8-alkyl compounds thus providing as final compounds,l7oz-(3- chloropropynyl l 7B-acetoxyl 8methylestr-4-en-3 one l7a-( 3-chloropropynyl 1 7/3-acetoxyl 8- ethylestr-4-en-3-one,l7a-(3-chloropropynyl)-17,8- acetoxy-l 8-n-propylestr-4-en-3-one.

PREPARATION 2 To a slurry of 1.0 g. of sodium hydride in vl ml. of drydiethyleneglycol dimethyl ethqr under a dry nitrogen atmosphere isslowly added 1.0 g. of 3- methoxy-l 7a-ethynylestra-l ,3,5( l0)-trien- 173-01 in ml. of dry diethylne glycol dimethyl ether in a dropwisefashion over a 20 minute period. To this mixture is added dropwise, 0.9g. of 2-chlorotetrahydropyran over a 10 minute period.

The mixture is stirred at room temperature for an additional 30 minutesand then cautiously added to an icewater mixture with stirring. Theorganic phase is extracted with diethyl ether, dried and evaporatedunder reduced pressure to yield 3-methoxy-l7a-ethynyl-l 7B-tetrahydropyran-2 '-yloxyestrl ,3 ,5 lO)-triene which may be furtherpruified via recrystallization from acetonezhexane.

Two milliliters of dihydropyran are added to a solution of l g. of3-methoxy-l7a-ethynylestra-l,3,5(l0)- trien-17B-ol-3-one in ml. ofbenzene. About l ml. is removed by distillation to remove moisture and0.4 g. of p-toluene-sulfonic acid is added to the cooled solution. Thismixture is allowed to stand at room temperature for 4 days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on netural alumina, elutingwith hexane, to yield 3- methoxy-l 7a-ethynyll 7B-tetrahydropyran-2-yloxyestra-l,3,5(l0)-tirene which is recrystallized from pentane.

A solution of 2.5 grams of phenyllithium in 25 ml. of diethyl ether isprepared. While maintaining this solution at room temperature, 10 gramsof 3-methoxy-l 7aethynyll 7fl-tetrahydropyran-240 -yloxyestrl,3,5(l0)-triene are added thereto to provide a solution containing3-methoxy-l 7a-ethynyllithium- 1 7B- tetrahydropyran-2'-yloxyestr-l,3,5( l0)-triene. To the resulting solution is added, portionwise andwith stirring, 3 grams of paraformaldehyde. The addition is conducted ata rate to maintain gentle reflux of the solution. After the addition,the mixture is stirred for hours, and then poured into water andextracted with ether. The ether is washed with water, dried andevaporated to obtain the 3-methoxy-l7a-(3-hydroxypropynyl l7B-tetrahydropyran-2 -yloxyestr-l ,3 ,5 l0)-triene product.

3-Methoxyl 7a-(3-hydroxypropynyl 1 7B-tetrahydro-pyran-2'-yloxyestra-1,3,5( lO)-triene l g.) is dispersed in50 ml. of anhydrous ether at room temperature with stirring. To theresultant solution is added 1.5 ml. of purified thionyl chloride. Theaddition is conducted portionwise at 0C. The resulting reaction mixtureis then allowed to stand at 0C. for a period of 6 minutes after whichtime it is washed with aqueous sodium bicarbonate solution followed bywater. The washed material is then dried over sodium sulfate andevaporated to dryness to obtain the 3-methoxy-l7a-(3- chloropropynyl l 7B-tetrahydropyran-2 '-yloxyestra- 1,3,5( lO)-triene product which isrecrystallized from etherzethyl acetate.

Alternatively, the l7oz-(3-chloropropynyl) compound is prepared asdescribed in Preparation 3.

To a solution of 1 g. of 3-methoxy-l7a-(3- chloropropynyl l7B-tetrahydropyran-2 -yloxyestral,3,5( l0)-triene in ml. of acetic acidis added 0.5 ml. of 2 N hydrochloric acid. The mixture is allowed tostand 5 hours at room temperature and then diluted with ice water andextracted with methylene chloride. The extracts are washed with water toneutrality, dried over sodium sulfate, and evaporated to dryness toyield 3 -methoxy-,l 7a-( 3-chloropropynyl )-estra-l ,3 ,5 l0

trien-l7B -ol which is recyrstallized from acetone:hex-

ane.

PREPARATION 3 Alternative to the procedures described in Preparations 1and 2, the following can be employed to prepare the 3-chloropropynylcompounds:

A solution of l7a-(3-hydroxypropynyl)-l7,8-acetoxyestr-4-en-3-one (3.5g.) and triphenylphosphine (4.2 g.) in dimethylforrnamide (26.7 ml.)containing carbon tetrachloride (1.1 ml) is heated at llOfor 15 minutesand then the solvent is evaporated under reduced pressure. The residueis dissovled in hexane-ether (3:1) and chromatographed on 140 g. ofsilica gel. Elution with ether-hexane (2:1) and crystallization of thepooled crystalline fractions from hexane furnishes l7a-(3-chloropropynyl)- l 7B-acetoxyestr- 4-en 3-one.

In accordance with the above procedure, 17a-(3chloropropynyl)-estr-4-en-l7a-ol-3-one is prepared froml7a-(3-hydroxypropynyl)-estr-4-en-l7B-ol-3- one.

Similarly, l7a-(3-chloropropynyl)-17,8-acetoxy-l 8methylestr-4-en-3-one, '6,6-difluoro- 1 7a-( 3- chloropropynyl)- l7/3-acetoxy-estr-4-en-3-one, and6,6-difluoro-17a-(3-chloropropynyl)-l7B-acetoxy-l 8-methylestr-4-en-3-one are prepared. Base hydrolysis thereof affords thecorresponding l7B-ols or the chlorination can be performed on thel7B-ol.

PREPARATION 4 1 7a-( 3-Hydroxypropynyl )-estr-4-enl 7B-ol-3-one l.5 g.)is dissovled into ml. of toluene. The resulting solution is mixed with 2g. of benzene sulfonyl fluoride. The reaction mixture is then heated toa temperature ranging from to C. and for a period of 4 hours. At the endof this reaction period, the mixture is cooled and then poured into icewater. The organic layer is then washed with a sodium bicarbonatesolution and then with water and, following the washings, is dried oversodium sulfate. Solvent is then removed by which can be recrystallizedfrom acetonezhexane.

Alternatively, the above method is practiced in acetonitrile at roomtemperature for about 24 hours or with tetrahydrofuran at reflux forabout 1 hour.

PREPARATION A solution of 3-tetrahydropyran-2'-yloxyprop-l-yne (7.1 g.)in dry tetrahydrofuran (50 ml.) is added to a solution of ethylmagnesiumbromide prepared from ethyl bromide (4.0 g.) and magnesium turnings (0.9g.) in tetrahydrofuran (75 ml.). The reaction mixture is heated underreflux for 5 minutes and after being allowed to stand at roomtemperature for 30 minutes it is treated with a solution of3-ethoxyestra-3,5-dien-l7- one (5.0 g.) in dry tetrahydrofuran (65 ml.).After 8 hours, acetyl chloride (20 ml.) is added and the reactionmixture is kept at room temperature for 18 hours and then poured intowater. The crude product, isolated by extraction with methylenedichloride, is dissolved in methanol 15 ml.) containing 0.25 ml. ofconcentrated hydrochloric acid and the resulting solution heated underreflux for minutes. Addition of water (200 ml.) and isolation byextraction with methylene dichloride furnishes a crystalline solid whichis purified by chromatography over Florisil (200 g.). Elution with ethylacetate-hexane (1:4) givesl7a-(3-hydroxypropynyl)-l7B-acetoxyestr-4-en-3-one after crystallizationfrom ether.

The thus prepared compound is treated in accordance with thechlorination procedures of Preparation 2 or Preparation 3 to givel7a-(3-chloropropynyl)-l7B-acetoxyestr-4-en-3-one. In a similar mannerbut with elimination of the acetyl chloride treatment step, l7a-(3-chloropropynyl )-estr-4-enl 7,B-ol-3-one is prepared.

In accordance with the above procedures, l7a-(3-chloropropynyl)-17fl-acetoxy-l 8-methylestr-4-en-3- one, l7a-(3-chloropropynyl )-1 8-methylestr-4-en- 1 7B- ol-3-one, 6,6difluoro-17a-(3-chloropropynyl)-l7B- acetoxyestr-4-en-3-one, 6,6-difluoro- 1 7a-( 3- chloropropynyl )-estr-4-enl 7,6-ol-3-one,6,6-difluor- 1 7a-( 3-chloropropyny1)- l 7B-acetoxy-l 8-methy1estr-4-en-3-one, and 6,6-difluoro-l7a-(3-chloropropynyl)-l8-methylestr-4-en-l7/3-ol -3-one are prepared from the respectivestarting compounds. The 173-01 compounds can also be prepared upon finalbase hydrolysis of the l7fl-acetate products.

PREPARATION 6 l 7a-( 3-Bromopropynyl)-androst-4-en- 1 73-01 is preparedby substituting thionyl bromide for thionyl chloride in Preparations land 2 and by substituting carbon tetrabromide for carbon tetrachloridein Preparation 3. This can be acetylated to the 17B- acetate. Likewise,by employing the appropriate starting compounds, the corresponding18-methyl, -ethyl, and -propyl derivatives are prepared. Similarly,these procedures are applicable in the preparation of thel7a-(bromopropynyl) derivatives in the estrogen and estrane series.

PREPARATION 7 To a suspension of l g. of estr-4ene-3,l7-dione in 7.5 ml.of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshlydistilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. Themixture is stirred at room temperature for 15 minutes and allowed tostand at room temperature for 30 minutes. There is then added 0.8 ml. ofpyridine, followed by water until solidification occurs. This solid iscollected by filtration, washed with water and air dried to yield3-ethoxyestra-3,5-dien-l7-one which is recrystallized fromacetonezhexane.

A stream of perchloryl fluoride is passed through a solution of l g. of3-ethoxyestra-3,5-dien-l7-one in'25 m1. of dimethylformamide, cooled to0C., for 5 minutes. After being allowed to slowly attain a temperatureof 20C, the solution is poured into water and extracted with ethylacetate. These extracts are washed with saturated aqueous sodiumbicarbonate solution and with water to neutrality, dried over sodiumsulfate and evaporated to dryness. The residue is then chromatographedon alumina to separate the 6a-fluoro and 6B-fluoro isomers. The latter,which predominates, is dissolved in 50 ml. of glacial acetic acid andthrough this solution is passed a stream of dry hydrogen chloride for aperiod of 24 hours and at a temperature of 15C. The mixture is pouredinto cold water and the solid which forms is collected by filtration,washed withwater and dried to yield 6a-fluoroestr-4-ene-3,l7- dionewhich is recrystallized from acetonezhexane.

To a suspension of l g. of 6a-fluoroestr-4-ene-3,-l7'- dione in 7.5 ml.of anhydrous, perioxide-free dioxane are added 1.2 ml. of freshlydistilled ethyl orthoformate and 0.8 g of p-toluenesulfonic acid. Themixture is stirred at room temperature for 15 minutes and allowed tostand at room temperature for 30 minutes. There is then added 0.8 ml. ofpyridine, followed by water until solidification occurs. This solid iscollected by filtration, washed with water and air dried to yield3-ethoxy- 6-fluoroestra-3,5-dien-l 7-one which is recrystallized fromacetonezhexane. I

A stream of perchloryl fluoride is passed through a solution of 1 g. of3-ethoxy-6-fluoroestra-3,5-dien-l7- one in 25 ml. of dimethylformamide,cooled to 0C., for 5 minutes. After being allowed to slowly attain atemperature of 20C., the solution is poured into water and extractedwith ethyl acetate. These extracts are washed with saturated aqueoussodium bicarbonate solution and with water to neutrality, dried oversodium sulfate and evaporated to dryness. The residue is thenchromatographed on alumina to provide the 6,6

difluoroestr-4-ene-3, l 7-dione product on recrystallization fromacetonezhexane.

In like manner, 6,6-difluoroandrost-4-ene-3, l 7- dione, 6,6-difluorol8-methylestr-4-ene-3, l 7-dione, 6,6-difluoro-l 8-methylandrost-4-ene-3,l 7-dione, 6,6- difluorol 8ethyl-estr-4-ene-3 l 7-dione, 6,6-difluorol8-ethylandrost-4-ene-3, l 7-dione, 6,6-difluoro-l 8-propylestr-4-ene-3,l7-dione and 6,6-difluoro-l 8-propylandrost-4-ene-3,l7-dione are prepared from the respective startingcompound.

PREPARATION 8 A solution of 2 g. of 6,6-difluoroestr-4-ene-3,l7- dionein 20 ml. of anhydrous tetrahydrofuran is cooled to -75C. in dryice-acetone bath and treated with a previously cooled solution of 0.6 g.of lithium tri-t-butoxy aluminum hydride in 20 ml. of anhydroustetrahydrofuran. After maintaining the reaction mixture at reflux for 15minutes it is cooled and poured into ice water and extracted severaltimes with ethyl acetate. These extracts are washed with water toneutrality, dried over anhydrous sodium sulfate and evaporated todryness to yield 6,6-difluoroestr-4-ene- 3,l7B-diol.

A mixture of 3 g. of 6,6-difluoroestr-4-ene-3Bl7B- diol, ml. of pyridineand 0.9 ml. of acetic anhydride is allowed to stand at room temperaturefor hours. The mixture is then poured into ice water and the solid whichforms is collected by filtration, washed with water and dried to yield3B,l7B-diacetoxy-6,6- difluoroestr-4-ene;3B-acetoxy-6,6-difluoroestr-4-en- 1 73-01, and 6,6-difluorol7B-acetoxyestr-4-en-3B-ol which are separated by chromatography onalumina.

A solution of 6 g. of 3H-acetoxy-6,6-difluoroestr-4- en-l7B-ol in 120ml. of pyridine is added to a mixture of 6 g. of chromic trioxide in ml.of pyridine. The reaction mixture is allowed to stand at roomtemperature for 15 hours, diluted with ethyl acetate and filteredthrough Celite diatomaceous earth. The filtrate is washed well withwater, dried and evaporated to dryness to yield3B-acetoxy-6,6-difluoroestr-4-en-l7-one which may be further purified byrecrystallizaton from acetone: hexane.

In like manner, 3B-acetoxy-6,6-difluoro-l8- methylestr-4-en-l7-one isprepared from 6,6-difluorol8-methylestr-4-ene-3 l 7-dione.

The thus-prepared compounds are treated in accordance with theprocedures set forth in Preparations 1, paragraphs 3 and 4 to preparethe 3B,l7B-diacetoxy- 6,6-difluoro- 1 7a-( 3-hydroxypropynyl)-estr-4-ene which is converted to the corresponding l7a-(3-halopropynyl) derivatives via the procedures set forth in Preparationsl, 2, 3, 4, 6, and 16. Thus prepared are 3B, 17B-diacetoxy-6,6-difluoro-l 7a-( 3-halo-propynyl estr-4-ene and3,8,17B-diacetoxy-6,6-difluorol7a-(3- halopropynyl l 8-methylestr-4-ene.Also thus prepared is 3,8,17fl-diacetoxy-6,6-difluoro-l7a-(3-halopropynyl)-androst-4-ene.

Substitution of an alternate carboxylic acid anhydride in the aboveprocedures affords the correspoinfing diacylates, for example, thepropionates, benzoates, pentanoates, and adamantoates, for example,

33,17,8-dipropionyloxy-6,6-difluoro-l7a-(3- halopropynyl)-estr-4-ene,

38,1 7B-dipropionyloxy-6,6-difluoro- 1 7a-( 3- halopropynyl)- l8-methylestr-4-ene,

3,8, l 7B-acetoxy-6,6-difluoro-l 7a-( 3-halopropynyl l8-ethylestr-4-ene,

3 B, l 7B-dipropionyloxy-6,6-difluoro- 1 7a-( 3- halopropynyl)-androst-4-ene,

3/3, 1 7B-dibenzoyloxy- 1 7B-( 3-halopropynyl )-estr-4- ene,

33, l 7B-dibenzoyloxy-6,6-difluoro- 1 7B-( 3- halopropynyl)-estr-4-ene,

3,8, l 7B-dibenzoyloxy-6,6-difluoro- 1 7a-( 3- halopropynyl l8-methylestr-4-ene, and

3 B l 7B-dibenzoyloxy- 1 7a-( 3-halopropynyl l 8- methylandrost-4-ene.

PREPARATION 9 A solution of 1 gram of sodium borohydride in 3 ml. ofwater is added to an ice-colled solution of 1 gram of6,6-difluoroestr-4-ene-3,l7-dione 'in 120 ml. of methanol and themixture is then allowed to stand for 16 hours at room temperature. Theexcess reagent is decomposed by the addition of acetic acid and thesolution is then concentrated to a small volume in vacuum and dilutedwith water. The product is extracted with ethyl acetate and theseextracts are washed with water, dried and evaporated to yield6,6-difluoroestr-4-ene-3 B,l7,B-diol which may be further purified byrecrystallization from acetone:hexane.

To a slurry of 1.0 g. of sodium hydride in 10 ml. of drydiethyleneglycol dimethyl ether under a dry nitrogen atmosphere isslowly added 1.0 g. of 6,6- difluoroestr-4-ene-3/3,l7B-diol in 10 ml. ofdry diethyleneglycol dimethyl ether in a dropwise fashion over a 20minute period. To this mixture is added dropwise, 0.9 g. of2-chlorotetrahydropyran over a 10 minute period. The mixture is stirredat room temperature for an additional 30 minutes and then cautiouslyadded to an ice-water mixture with stirring. The or ganic phase isextracted with diethyl ether, dried and evaporated under reducedpressure to yield 3,8,173- bis-(tetrahydropyran-2-yloxy)-6,6-difluoroestr-4-ene;3B-tetrahydropyran-2-yloxy-6,6-difluoroestr-4-en- 1 713-01; and6,6-difluorol 7B-tetrahydropyran-2-yloxyestr-4-en-3fl-ol, which areseparated by chromatography on alumina.

Substitution of dihydrofuran in the above procedure prepares thecorresponding tetrahydrofuran-2-yloxy derivatives.

A solution of 6 g. of 3B-tetrahydropyran-2.-yloxy-6,6-difluoroestr-4-en-l7B-ol in 120 ml. of pyridine is added to amixture of 5 g. of chromic trioxide in 20 ml. of pyridine. The reactionmixture is allowed to stand at room temperature for 15 hours, dilutedwith ethyl acetate and filtered through Celite diatomaceous earth. Thefiltrate is washed well with water, dried and evaporated to dryness toyield 3B-tetrahydropyran-2- yloxy-6,6-difluoroestr-4-en-l7-one which maybe further purified by recrystallization from acetone:hex-

ane.

To a solution of 1 gram of lithium aluminum hydride in ml. of anhydroustetrahydrofuran is continuously bubbled a slow current of purifiedacetylene for one hour. Thereafter, 1 gram of SB-tetrahydropyran-Z'-yloxy-6,6-difluoroestr-4-en-l7-one in 10 ml. of tetrahydrofuran isadded and the reaction mixture stirred at room temperature for fourhours. Eight milliliters of water is then added and the mixture isstirred for 30 minutes. The mixture is then, filtered and the organicfiltrate evaporated to yield 3B-tetrahydropyran-2 '-yloxy-6,6-difluorol7a-ethynylestr-4-enl 7B-ol which is recrystallized from acetonezhexane.

In a similar manner, 3B-tetrahydrofuran-2-yloxy- 6,6-difluorol7a-ethynylestr-4-en- 1 73-0] is prepared.

The thus prepared 3B-tetrahydropyran-2'-yloxy-6,6- difluorol7a-ethynylestr-4-enl 7B-ol and 3B- tetrahydrQfuran-Z-yloxy-6,6-difluoro-l 7a-ethynylestr- 4-en- 1 73-01 compounds are thentreated in accordance with the procedure of Preparation 2 (paragraph 4)followed by the halogenation procedures set forth in Preparations l to4, 6, or 16 to respectively form 3,8- tetrahydropyran-2'-yloxy-6,6-difluoro-. 1 7a-( 3- halopropynyl)-estr-4-en-l73-01 and3fl-tetrahydrofu-' ran-2'-yloxy-6,6-difluoro- 1 7a-(3-halopropynyl)-estr-4- en-17fl-ol.

The thus prepared 3B-monoethers can -be then acylated as describedin-Preparation 8 above to prepare the mixed ester-ether derivatives.Thus formed, for example, are 3fl-tetrahydropyran-2'-yloxy-6,6-difluorol7a-( 3-halopropynyl l 7B-acetoxyestr-4-ene, 3B- tetrahydrofuran-2'-yloxy-6,6-difluoro- 1 7a-( 3- halopyopynyl l 7B-acetoxyestr-4-ene, 3B- tetrahydropyran-2 '-yloxy-6,6-difluoro- 1 7a-( 3- halopropynyl )-l7B-acetoxyandrost-4-ene, 3B- tetrahydrofuran-2 '-yloxy-6,6-difluoro- 17a-( 3- halopropynyl l 7B-acetoxyandrost-4-ene, 3,8- tetrahydropyran-2'-yloxy-6,6-difluoro- 1 7a-( 3- halopropynyl)- l7l3-propionyloxyestr-4-ene, 3/3- tetrahydrofuran-Z -yloxy-6,6-difluoro 17a-( 3- halopropynyl 1 7B-propionyloxyestr-4-ene, 3B- tetrahydropyran-2-yloxy-6,6-difluoro- 1 7a-( 3- halopropynyl)- l7B-propionyloxyandrost-4-ene, 3B- tetrahydrofuran-2 -yloxy-6,6-difluoro-1 7a-( 3- halopropynyl l 7fl-caproyloxyestr-4-ene, 3B- tetrahydropyran-2'-yloxy-6,6-difluoro- 1 7a-( 3- halopropynyl I 7B-carproyloxyestr-4-ene,3B- tetrahydrofuran-2 '-yloxy-6,6-difluoro-l 7a-( 3- halopropynyl l7/3-caproyloxyestr-4-ene, 3 [3- tetrahydropyran-2 -yloxy-6,6-difluoro- 17a-( 3- h'aloprolpyny'D-l 7fl-caproyloxyestr-4-ene, 3B-

tetrahydrofuran-2 '-yloxy-6,6-difluoro-l 7a-( 3- halopropynyl)- l7B-caproyloxyandrost-4-ene, and so forth.

PREPARATION 10 The compound 3fl-acetoxy-6,6-difluoroestr-4-enl 7- one istreated in accordance with the procedure set forth in paragraph ofPreparation 9 to prepare 3B- acetoxy-6,6-difluoro-l 7a-ethynylestr-4-en-1 73-01.

This derivative is then etherified in accordance with the procedureset'forth in paragraphs 2 or 3 or Preparation 9 to respectively preparethe corresponding 3B-acetoxy-6,6-difluoro l 7a-ethynyl-l7'n-tetrahydropyran-2'- yloxyestr-4-ene and 3B-acetoxy-6,6-difluorol7a-ethynyll 7B-tetrahydrofuran-2 '-yloxyestr-4-ene.

In like manner, the foregoing procedures can be followed with the otherstarting 3B-acylates described in the foregoing procedures.

chloropropynyl)-estr-4-ene,

PREPARATlON-l 1 cargonate solution and water, dried and evaporated.

The residue is chromatographed on neutral alumina,

eluting with hexane, to yield 6,6-difluoro-l7a-ethynyl-17B-tetrahydropyran-2-yloxyestr-4-en-3-one which is recrystallized frompentane.

A solution of 2 g. of 6,6-difluoro-l7a-ethynyl-l762tetrahydropyran-2-yloxyestr-4-en-3-one in 20 ml. of anhydroustetrahydrofuran is cooled to -75C. in a dry ice-acetone bath and treatedwith a previously cooled solution of 0.6 g. of lithium tri-t-butoxyaluminum hydride in 20 ml. of anhydrous tetrahydrofuran. Aftermaintaining the reaction mixture at reflux for 15 minutes, it is cooledand poured into ice water and extracted several times with ethylacetate.These extracts are washed with water to neutrality, dried over anhydroussodium sulfate and evaporated to dryness to yield 6,6-difluoro--b'l7a-ethynyl-17B- tetrahydropyran-2-yloxyestr-4-en-3B-ol.

To a slurry of 1.0 g. of sodium hydride in 10 ml. of drydiethyleneglycol dimethyl ether under a dry nitrogen atmosphere isslowly added 1.0 g. of 6,6-difluro- 1 7a-ethynyll 7,8-tetrahydropyran-2-yloxyestr-4- en-3B-ol in 10 ml. of dry diethyleneglycol diemthyl etherin a dropwise fashion over a 20 minute period. To this mixture is addeddropwise, 0.9 g. of 2- chlorotetrahydropyran over a 10 minute period.

The mixture is stirred at room temperature for an additional 30 minutesand then cautiously added to an ice-water mixture with stirring. Theorganic phase is extracted with diethyl ether, dried andevaporated underreduced pressure to yield 313,17B-bistetrahydropyran- 2'-yloxy-6,6-difluorol 7a-ethynylestr-4-ene which may further purified 1via recrystallization from acetonezhexane. r v

Two milliliters of dihydropyran are added to a solution of l g. of6,6-difluoro-l7a-ethynyl-l 7fitetrahydropyran-2'-yloxyestr-4-en--3B-olin 15 ml. of benzene. About 1 ml. is removed by distillation to removemoisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays, and is then washed with aqueous soduim .carbonate solution andwater, dried and evaporated. The residue is chromatographed on neutralalumina, eluting with hexane, to yield3/3,l7B-bistetrahydropyran-2'-yloxy- 6,6-difluorol 7a-ethynylestr-4-enewhich is' recrystal lized from pentane. g

The thus prepared compound is then treated in accordance with theprocedure set forth, for example, in Preparation 2, paragraph 4- to 0give bistetrahydropyran-2'-yloxy-6,6-difluorol Z-( 3-hydroxypropynyl)-estr-4-ene which is, in turn, halogenated via theprocedures described in Preparations 1 to 4, 6, and 16 to give thecorresponding 17a- -(3-halopropynyl) compounds, e.g.,33,17B-bistetrahydropyran-Z -yloxy-6 .6-difluoro-l 7a-(3- andbistetrahydropyran-2 '-yloxy-6,6-difluoro-- 17a-(3- bromopropynyl )-estr1 4-ene, and 33,173- bistetrahydropyran-2 -yloxy-6,6-difiuoro- 1 7a-( 3-fiuoropropynyl )-estr-4-ene.

PREPARATION 12 One gram of estr-5( lO)-ene-3,l7-dione is suspended in 10ml. of anhydrous methanol containing 0.16 ml. of perchloric acid (70percent) per liter of methanol. The reaction mixture is stirred at roomtemperature and under anhydrous conditions overnight. Solid sodiummethoxide is then added and the reaction mixture is then slowly dilutedwith from 5 to 10 times its volume with water. The mixture is thenfiltered to give 3,3- dimethoxyestr-5( l)'en-l7-one which can berecrystallized from methylene chloridezmethanol containing a trace oftriethylamine.

The thus prepared compound is then treated in accordance with'theprocedures of Preparation 1 to give 3 ,3-dimethoxy- 1 7a-(3-tetrahydropyran-2'-yloxypropynyl)-estr-(10)-en-l7B-ol.

One gram of 3 ,S-dimethoxy- 1 7a-( 3- tetrahydropyran-2-yloxypropynyl)-estr-5( )-en- 1 7B- ol is dispersed in 45 ml. of acetonecontaining 0.05 mg. of malonic acid in 5 ml. of water and the resultantmixture is allowed to stand at room temperature overnight. After thistime, it is poured into dulute aqueous potassium bicarbonate solutionand extracted with ether. The extracts are dried and evaporated to givel7a-(3- hydroxypropynyl)-estr-5( 10)-enl 7B-ol-3-one.

The thus prepared compound is then halogenated as described above, withor without prior conversion to the l7B-acetate, to give thecorresponding 3- halopropynyl compounds, e.g.,l7a-(3-chloropropynyl)-estr-5( l0)-enl 7B-ol-3-one.

The foregoing hydrolysis can be practiced upon the product ofPreparation 1 l to give 6,6-diflu0ro-l7a-(3-chloropropynyl)-estr-4-ene-3B,l 7B-diol. 6,6-Difluoro- 17a-(3-bromopropynyl )-estr-4-ene-3B, l 7/3-diol and6,6-difluoro-l7a-(3-iodoor fluoropropynyl)-estr-4- ene-3B,l 7B-diol arealso thus prepared from the respective halo starting compounds.

One gram of 6,6-difluoro-17a-(3-chloropropynyl)-ester-4-ene-3B,l7fi-diol in 100 ml. of chloroform which has beendistilled over calcium chloride, is stirred for 18 hours at roomtemperature with 10 g. of freshly precipitated manganese dioxide. Theinorganic material is then removed by filtration and washed with hotchloroform and the combined filtrate and washings are evaporated toyield 6,6difluoro-l7a-(3- chloropropynyl)-estr-4-en-17B-ol-3-one whichmay be PREPARATION l 3 A mixture of l g. of l7B-acetoxyestr-4-en-3-one,25 ml. of dry benzene, 5 ml. of ethylene glycol, and 50 mg. ofp-toluenesulfonic acid monohydrate is refluxed for 16 hours using awater separator. The reaction mixture is then washed with aqueous sodiumbicarbonate solution and water, dried and evaporated to dryness. Theresultant residue is chromatographed on alumina eluting withhexanezbenzene and pure benxene to yield 3,3-ethylenedioxy-l7/3-acetoxyestr-5( lO)-ene which is recrystallized fromacetone:hexane.

To a solution of 1.0 g. of 3,3-ethylenedioxy-l7/3- acetoxyestr-5(l0)-enein 50 ml. of benzene is added 0.2 g. of magnesium sulfate. Thee mixtureis heated at reflux for 40 minutes, neutralized with a saturated aqueoussodium carbonate solution, concentrated under reduced pressure to about20 ml. and poured into water. The solid which forms is collected byfiltration, washed well with with water, and dried to yieldl7B-acetoxyestr-5( lO)-en-3-one which may be recrystallized fromacetone.

One gram of 3,3-ethylenedioxy-l7B-acetoxyestr- 5( l0)-ene 10)- isdispersed in 45 ml. of acetone containing 0.05 mg. of malonic acid in 5ml. of water and the resultant mixture is allowed to stand at roomtemperature overnight. After this time it is poured into dilute aqueouspotassium bicarbonate solution and extracted with ether. The extractsare dried and evaporated to give l7B-acetoxyestr-5( l0)-en-3-one.

To a solution of 0.2 g. of l7,B-acetoxyestr-5( lO)-en- 3-one in 4 ml. ofpyridine is added 1.1 g. of pyridine perbromide hydrobromide. Themixture is stirred at room temperature for 7 hours after which time itis partitioned between water and ethyl acetate and the organic phaseseparated. This is washed successively with dilute hydrochloric acid,dilute sodium bicarbonate solution, dried and evaporated. The resultantsolid is chromatographed on alumina eluting with benzenezether and purebenzene to give l7B-acetoxyestra-4,9( lO)-dien-3-one.

A solution of l g. of l7/3-acetoxyestra-4,9(10)-dien- 3-one in 50 ml. ofmethanol is heated at reflux for 3 hours with a solution of potassiumhydroxide in 1 ml. of water. The reaction mixture is then poured intoice water and the solid which'forms collected by filtration, washed withwater to neutrality and dried to yield estra- 4,9( l0)-dien-l7B-ol-3-onewhich is recrystallized from methylene chloridezether.

A solution of 6 g. of estra-4,9( l0)-dien-l7B-ol-3-one in 120 ml. ofpyridine is added to a mixture of 6 g. of chromic trioxide in 20 ml. ofpyridine. The reaction mixture is allowed to stand at room temperaturefor 15 hours, diluted with ethyl acetate, and filtered through water,dried and evaporated to dryness to yield estra-4,9-(l0)-diene-3,l7-dione which may be further purified byrecrystallization from acetonezhexane.

Likewise, l8-methylestra-4,9(l 0)-diene-3 l 7-dione, l8-ethylestra-4,9(l0)-diene-3,20-dione and l 8- propylestra-4,9( lO)-diene-3 l 7-dione areprepared.

Estra-4,9(10)-dien-l7[3-ol-3-one (2 g.) is added to a solution ofhydrogen chloride (1 g.) in methanol ml.). After 15 minutes at roomtemperature, the solution is cooled in ice and is neutralized withpowdered sodium methoxide. Methylene chloride (300 ml.) is then addedand the mixture is washed several times with water. The dried solvent isevaporated and the residue is exahustively extracted with boilingn-hexane. The extract is chromatographed on Florisil (50 g.). The columnis eluted with l, 2, 3, and 4 percent acetone in petroleum ether (b.p.-30-60). The residue eluted in the latter is dissolved in acetone (40ml.) and the solution is treated with sulfuric acid (0.5 ml.; 8percent). After 5 minutes, the mixture is diluted with water and thecrystals which separate are collected, washed with water, and dried.Recrystallization from n-hexane give the estra-5( l),9( 1 l)-dien-17B-ol-3-one.

A solutuion of 6 g. of estra 5( l0),9(] l)-dien- 1 713-01- 3-one in 120ml. of pyridine is added to a mixture of 6 g. of chromic trioxide in 20ml. of pyridine. The reaction mixture is allowed to stand at roomtemperature for 15 hours, diluted with ethyl acetate and filteredthrough Celite diatomaceous earth. The filtrate is washed well withwater, dried and evaporated to dryness to yield estra-5(l0),9(11)-diene-3,l7-dione which may be further purified by recrystallizationfrom acetonezhexane.

Likewise, l8-methylestra-5( l0),9( l 1 )-diene-3,17- dionel8-ethylestra-5( l0),9( l l )-diene-3, l 7-dione, and l8-propylestra-5(l0),9( 1 l )-diene-3, l 7-dione are prepared.

A mixture of 2.0 g. of estra4,9( l0)-diene-3,l7- dione 100 ml. of drybenzene, 10 ml. of ethylene glycol and 250 mg. of p-toluenesulfonic acidmonohydrate is refluxed under nitrogen for 6 hours. The reaction mixtureis then washed with benzene, aqueous sodium bicarbonate solution, andwater, dried and evaporated to dryness to yield3,3;17,17-bisethylenedioxyestra- 5( l0),9(] l )-diene which, isrecrystallized from acetonezhexane.

The above procedure is repeated using estra- 4,9(10)-dien-l7B-ol-3-oneto give 3,3-ethylene dioxyestra-5( l0),9( l l )-dien-l7B-ol-3-one whichis oxidized with Collins reagent as described above to give3,3-ethylenedioxyestra-5( l0),9( l l)-dienl 7-one.

To a solution of 1.75 g. of 3,3; l7,17-bisethylenedioxyestra-5(l0),9(l1)-diene in 5 ml. of methylenechloride is added 1.2 g. of m-chloroperbenzoic acid. The reactionmixture is kept at room temperature for 20 minutes. The mixture is thenextracted with methylene chloride, the extracts washed with dilutesodium bicarbonate solution and water, and evaporated to yield to oil.

' The oil thus obtained is chromatographed on silica with 1:1 ethylacetatezhexane and is then dissolved in 4 ml. of dioxane and treated at25C. with 0.05 ml. of perchloric acid (70 percent) for 20 minutes.Isolation via chromatography yields estra'4,9( l0),l l-trien'e-3,17-dione.

Similar results are obtained when perbenzoic'acid is substituted form-chloroperbenzoic acid in the epox-' idation procedure. In like manner,sulfuric acid or other strong acid can be substituted in lieu ofperchloric acid in the last procedure with successful results.

The oil obtained upon epoxidation as described above is alternatelydissolved in 100 mg. of ptoluenesulfonic acid. The mixture is kept atroom temperature for 20 hours and is then evaporated to an oily mixturecontaining the corresponding hydroxy derivatives. These latterderivatives may be isolated via chromatography or the oil may be treatedwith perchloric acid or other mineral acid as described above tosimilarly yield estra-4,9( l0),l l-triene-3, 1 7-dione.

Like prepared by the procedures of this example is l8-methylestra4,9(l0),l l-triene-3, l 7-dione.

A solution of 2 g. of estra-4,9(l0),l l-triene-3,l7- dione in 20 ml. ofanhydrous tetrahydrofuran is cooled to -75C. in a dry ice-acetone bathand treated with a previously cooled solution of 0.6 g. of lithiumtri-t-butoxy aluminum hydride in 20 ml. of anhydrous tetrahydrofuran.After maintaining the reaction mixture at reflux forv 15 minutes it iscooled and poured into ice water and extracted several times with ethylacetate. These extracts are washed with water to neutrality, dried overanhydrous sodium sulfate and evaporated to dryness to yieldestra-4,9(10),l l-triene- 3,8,17B-diol.

A mixture of 1 g. of estra-4,9( l0),l l-triene-3B,17B- diol 4 ml. ofpyridine and 2 ml. of acetic anhydride is allowed to stand at roomtemperature for 15 hours'The mixture is then poured into ice water andthe solid which forms is collected by filtration, washed with water anddried to yield 3,8-acetoxyestra-4,9(l0),l1- trien-l7B-ol which isrecovered by chromatography 0 silica gel.

A solution of 6g. of 3B-acetoxyestra-4,9(l0),lltrien-17B-ol in 120 ml.of pyridine is added'to a mixture of 6 g. of chromic trioxide in 20 ml.of pyridine. The reaction mixture is allowed to stand at roomtemperature for 15 hours, diluted with ethyl acetate and filteredthrough Celite diatomaceous earth. The filtrate is washed well withwater, dried and evaporated to dryness to yield3B-acetoxyestra-4,9(l0),l l-trien-l7-one which may be further purifiedby recrystallization from acetonezhexane.

Alsothus prepared are 3B-acetoxy-l8-methylestra: 4,9( l0),-trien-l 70neand 3B acetoxy-l S-ethylestra- 4,9( l0),-trienl 7-one and BB-acetoxy-lS-propylestra-4,9( l0),l 1-trien-l7-one.

PREPARATION 14 ethylene ketal followed by oxidation with Collins rel7a-p-tolylsulfonyloxypropynyl )estra-4,9( 10),] 1-

trienl /B-ol-3-one, l 7a-p-tolylsulfonyloxypropynyl )estra-4,9(l)-dienl7B-ol-3-one, l7a-p-tolylsulfonyloxypropynyl)estra-5( l0)9( l ldien-l 7B-ol-3-one, 1 I 7a-p-tolylsulfonyloxypropynyl)-1 S-methylestra-4,9( l0),-trienl 7B-ol-3-one, l 7a-p-tolylsulfonyloxypropynyl 1S-methylestra- 4,9( lO)-dienl 7,8-ol-3-one, l7a-p-tolylsulfonyloxypropynyl )-l S-methylestra- 5( l0)9( l l)-dien-17B-ol-3-one, and so forth. The .foregoing .1 7B-hydroxycompounds can be esterified under conventional tertiary carbinolconditions to give the corresponding l7B-acetates thereof.

PREPARATION l5 Into a solution of 10 grams of 3,17-diacetoxy-l8-methylestr-S-ene in 120 ml. of dry carbon tetrachloride which ismaintained at 0C. is slowly bubbled nitro'syl fluoride over a period ofone-half hour. The reaction is monitored by tlc. After the reaction iscomplete, it is warmed until NO, is discharged. The reaction mixture isthen washed with water and extracted with methylene chloride. Theextracts are evaporated to dryness. The residue is recrystallized fromacetonezhexane. The recrystallized material (or total crude) ispercolated over 120 grams of aluminum oxide with benzene to give3,17-diacetoxy-5a-fluoro-l 8-methylestran-6-one.

To a solution of 3.2 grams of3,17-diacetoxy-5afluoro-l8-methylestran-6-one in 40 ml. of methylenechloride are added 80 grams of sulfur tetrafluoride. The reactionmixture is allowed to stand at room temperature overnight, in a pressureflask. After this time, the reaction flask is vented and the reactionmixture is poured into ice water and washed with 5 percent aqueoussodium bicarbonate solution. The washed material is dried over sodiumsulfate and evaporated to dryness, to give 3 l7-diacetoxy-5a,6,6-trifluorol 8-methylestrane.

3 ,17-Diacetoxy-5a,6,6-trifluoro-l8-methylestrane (2,6. g.) is dispersedin a solution of 50 ml. of methanol containing 4 ml. of concentratedhydrogen chloride. The resultant mixture is refluxed for 1.5 hours. Itis then diluted with water and the methanol eliminated under reducedpressure. The mixture is then cooled to room temperature and filteredand the precipitate washed with water and air dried. The material isthen dissolved in 50 ml. of acetone and treated with about 6 ml. of 8Nchromic acid in sulfuric acid without cooling. The mixture is thendiluted with water containing a trace of methanol and the solvent isthen eliminated under reduced pressure. The solid is collected and airdried.

Two grams of the resultant solid is dispersed in 75 ml. of methanolcontaining 6 grams of sodium acetate and the resultant mixture isrefluxed for 3 hours. The mixture is then diluted with water and thesolvent eliminated under reduced pressure. The mixture is then cooled toroom temperature and the solid collected by filtration and air dried togive 6,6-difluoro-l8- methylestr-4-ene3 l 7-dione.

The compound thus obtained is treated with 6 ml. of ethylene glycol, 2g. of oxalic acid, and 75 ml. of

benzene under reflux with the use of a water separator sodium sulfateand, after filtration, evaporated to dryness under reduced pressure. Theresidue is crystallized fractionally from acetonezhexane to give 3,3-ethylenedioxy-6,6-difluorol 8-methylestr-4-enl 7-one.

The resultant compound is then treated in accordance with the firstparagraph of Preparation 5 to give ypropynyl)-l8-methylestr-4-en-l7B-ol,after acetate hydrolysis. Alternatively, the l7B-acetate is preserved togive 3,3-ethylenedioxy-6,6-difluoro-l7a-(3-hydroxypropynyl l7,8-acetoxy-l 8-methylestr-4-en-3-one. This compound, or the 1713-01,can be converted to the corresponding l7a-(3-chloropropynyl) compoundsby the method of Preparation 3.

These compounds (ie., the l7a-(3-hydroxyor chloro-propynyl) can beketaliz'ed as set forth in Preparation 12, paragraph 1 or Preparation14,, paragraph The 3,3vdimethoxy and 3,3-ethylenedioxy compounds in thel7a-( 3-hydroxypropynyl) series can then be chlorinated (Preparation 3)to give the coresponding l7a-( 3-chloropropynyl )-6,6-difluoro ketalproducts, e-.g.

3,3-ethylenedioxy-6,6-difluoro-17a-(3-chloropropynyl)- 18-methylestr-4-en-17B-ol -3-one and 3,3-dimethoxy-6,6-difluoro-17a-(3-chloropropynyl)-l8-methylestr-4-en-l7B-ol-3-oneand the 17,8- acetates thereof.

In like manner the corresponding compounds in the l 3-methyl series areprepared.

PREPARATION 16 The following procedures illustrate the manner by whichthe l7d-(3-iodopropynyl) starting compounds are prepared by halogenexchange with sodium iodide.

A mixture of 1 gram of l7a-(3-bromopropynyl)-l7/3-acetoxyestr-4-en-3-one in 50 ml. of dry methylethyl ketonecontaining 1 g. of sodium iodide is refluxed for 10 hours. After thistime, the reaction mixture is poured into water and the resultantmixture extracted with ether. The ether extracts are washed with water,dried, and evaporated at 20C. in vacuum to give 1 7a-( 3-iodopropynyl l7/3-acetoxyestr-4en-3-one.

In like manner, the l7a-(3-chloropropynyl) starting compounds areconverted to the corresponding 17a- (3-iodopropynyl) compounds. Theforegoing reaction is repeated using acetone in lieu of. methylethylketone. with similar results.

EXAMPLE 1 3 ,3-ethylenedioxy-6,6-difluoro- 1 7a-( 3-hydroxlected byfiltration and recrystallized from acetonezhexane to obtain thel7a-propadienyl-l73- acetoxyestr-4-en-3-one product.

The foregoing procedure is repeated using l7B-(3- iodoorfluoropropynyl)-l7/3-acetoxyestr-4-en -3-one and l7a-(3-bromopropynyl)-l 7B-acetoxyestr-4-en-3- one to obtain the samel7a-propadienyl product. This can be hydrolyzed tol7a-propadienylestr-4-en-l75-0] -3-one.

In like manner, l7a-propadienyl-l8-methylestr-4- en-l7/3-ol-3-one,6,6-difluoro-l7a-propadienylestr-4- en-l 7B-ol -3-one, 6,6-difluoro-l7a-propadienyl-l 8- methylestr-4-en-l7B-ol-3-one, l7a-propadienylestra-5-(l),9(11)-dien-l7B-ol-3-one, l7a-propadienyl-l 8- methylestra-5(l0),9(i l )-dien-l 7B-ol-3-one, 17apropadienylestra-4,9(l0)-dien-l7fi-ol-3-one, 17apropadienyl-l 8-methylestra-4,9( l0)-dienl7,8-ol-3- one, i7a-propadienylestra-4,9( 10),] l-trien-l 73-01-3- one,and l7a-propadienyl-18-methylestra-4,9( l0),l ltrien-l7B-ol-3-one, areprepared from the respective 3- bromopropynyl, I i-fluoropropynyl,3-iodopropynyl, or 3-chloropropynyl starting compounds.

The foregoing procedure is practiced using glyme in lieu of glacialacetic acid and tetrahydrofuran in lieu of glacial acetic acid, withsimilar results. For example, i7a-(3-bromopropynyl)-l7fi-acetoxyestr-4-en-3-one is thus converted tol7a-propadienyl-l7B-acetoxyestr-4- en-3-one.

EXAMPLE 2 One gram of l7a-(3-chloropropynyl)-androst-4 -enl7B-ol-3-oneis dispersed in 50 ml. of ethanol at room temperature. Three grams ofcopper sulfate are dispersed in ml. of water and to the resultantaqueous solution is suspended 5 grams of zinc dust. The zinc-copperpowder formed from this suspension is added to the steroid ethanolsolution in a portionwise fashion at room temperature. Upon completionof the addition, the reaction mixture is heated to the boiling point andmaintained under reflux conditions for 16 hours. It is then filteredthrough Celite, the filtrate is collected and evaporated to dryness andthe residue crystallized from acetone:hexane to obtain the17apropadienylandrost-4-en-l 7/3-ol-3-one product.

The above procedure is repeated using l7a-(3-chloropropynyl)-estr-4-en-l7/3-ol-3-one to give17apropadienylestr-4-en-l7B-ol-3-one. Similarly, the 3- bromopropynyland 3-iodoor fluoropropynyl compounds are converted to the respectivel7a-propadienyl products.

In like manner, l7a-propadienyl-l8-methylestr-4- en-l7B-ol-3-one,6,6-difluoro-l7a-propadienylestr-4- en-i7B-ol-3-one, and6,6-difluoro-l7a-propadienyll 8-methylestr-4-en-17B-ol-3-one,l7oz-propadienylestra -5(10),9(11)- dien-l7B-ol-3-one,l7a-propadienyll8-methylestra-S-( 10),9( l l )-dien-l 7,B-ol-3-one,17apropadienylestra-4,9( l0)-dien-l 7B-ol-3-one, 17apropadienyl-l8-methylestra-4,9( l 0)-dien-l 713-01-3- one,l7a-propadienylestra-4,9(l0), 1l-trien-l7B-ol-3- one, andl7a-propadienyl-l8-methylestra-4,9(10),] ltrien-l 7B-ol-3-one, areprepared from the respective 3- bromopropynyl, 3-fluoropropynyl,3-iodopropynyl, or 3-chloropropynyl starting compounds.

Acetylation at C-17B provides the corresponding l7B-acetates, e.g.,l7a-propadienyll 7/3-acetoxyestr- 4-en-3-one, i7a-propadienyl-l7B-acetoxy-l 8- methylestr-4-en-3-one, 6,6-difluoro-l7a-propadienyll7B-acetoxyestr-4-en-3-one, 6,6-difluo'ro- 1 7apropadienyl-l'lB-acetoxy-l 8-methylestr-4-en-3-one,l7a-propadienyl-l7B-acetoxyestra-5( 10), 9(1 1 )-dien- 3-one,l7a-propadienyl-l 7B-acetoxy-l 8-methylestra-5 (l0),9(l l)-dien-3-one,l7a-propadienyl-l7B-acetoxyestra-4,9( l0 )-dien-3-one, l7a-propadienyll7,8- acetoxy-l 8-methyl-estra-4,9( lO)-dien-3-one, 17apropadienyl-l7Bacetoxyestra-4,9( 10),] i-trien-3-one, and i7a -propadienyl-l7B-acetoxyl 8-methylestra-4,9 (l0), ll-trien-3-one.

EXAMPLE 3 A steroid solution is prepared by dispersing 2 grams of 3methoxy-17a-(3-chloropropynyl)-estra-1,3,5( i0)- trien-l7B-ol in I00 ml.of isopropanol at room temperature with stirring. Five grams of finelydivided magnesium metal is added to the mixture in a portionwise fashionand at room temperature. The temperature of the resultant mixture israised to the boiling point and maintained under reflux and under anatmosphere of nitrogen for 24 hours. Upon completion of the reaction,excess magnesium is cautiously removed by filtration and the remaining'solution is washed with 5 ml. of isopropanol and then 5 ml of water. Theorganic layer is separated, dried over sodium sulfate, and evaporated todryness under reduced pressure. THe' residue is purified bychromatography over alumina and crystallized from methanolzbenzene toprovide the 3-methoxy-l7apropadienylestral ,3,5 )-trien-l 7B-ol product.

EXAMPLE 4 minutes following the addition, the acetone is removed.

under reduced pressure and water is added which in- .itiatesprecipitation. The precipitated solid is collected and dried over sodiumsulfate. The dried solid is thencrystallized from acetonezhexane toobtain the 6,6- difluoro-l 7a-propadienylestr-4-en-17B-ol-3-one product.

Alternatively, 6,6-difluoro-l7a-(3-chloropropynyl)- estr-4-en-3B,l7B-diol is reacted to give 6,6-difluorol7a-propadienylestr-4-ene-3B,l7B-diol which is oxidized, as described above, to give6,6-difluoro-l7apropadienylestr-4-en-l 7B-ol-3-one.

EXAMPLE 5 Two grams of l7a-(3-chloropropynyl')-estr-5(l0)-en-l7[3-ol-3-one is dispersed in a mixture of 50 ml. of anhydrousmethanol containing 25 g. of zinc dust. The thus prepared mixture isthen heated to the boiling point and maintained under reflux for 8hours, with stirring. It is then cooled and poured into water. Theaqueous mixture is then extracted with ethyl acetate and the extractsare separated and recovered and, upon EXAMPLE 6 A solution of 17a-(3-chloropropynyl-17B-acetoxyestr-4-en-3-one (2.8 g.) in anhydrousmethanol (50 ml.) is heated under reflux with zinc-copper couple (18.7g.) for 1 hour. The couple is prepared by treating 21.0 g. of zinc dustwith 1.2 g. of copper acetate in 30 I ml. of hot acetic acid at 90C. for3 minutes followed by cooling, removal of the acetic acid by decantationand acid. The solvent is evaporated under reduced pressure andtheresulting residue is purified by preparative tlc to givel70z-propadienylestr-4-en-l'IB-ol-El-one, after crystallization fromether-hexane.

In like manner, from l7a -(3-chloropropynyl)-17 8' acetoxy-l8-methylestr-4-en-3-one, 6,6difluoro-17a-(3- -acetoxy-l 8-methylestr-4-en-3-one there is respectively prepared l7a-propadienyll7B-acetoxyl 8-methylestr-4-en-3- one, 6,6-difluorol 7a-propadienyl-17B-acetoxyestr-4- en-B-one, and 6,6-difluorol 7a-propadienyl- 1 7B-acetoxy-l8-inethylestr-4-en-3-one which upon hydrolysis respectivelygive l7a-propadienyl-l8-methylestr- I 4-enl 7B-ol-3-one, 6,6-difluoro- 17a-propadienylestrl8-methylestr-4-en-17fl-ol-3-one.

l 7a-propadienylestra-5 l7a-propadienyl-18- Llkewise prepared are (1),9(1 1)-dienl 7B-ol-3-one, methylestra-( 10), 9( l l)-dien-17B-0l-3-one, 17apropadienylestra-4,9( l0)-dien-l 7B-ol-3-one,17apropadienyl-l 8methylestra-4,9( l0 )-dienl 713-01-3- one,l7a-propadlenylestra-4,9( l0), 1 l-trien- 1 75-01-3- one, and17a-propadienyl-l8methylestra-4,9( l0),l ltrien-17B-ol-3-one and thecorresponding 17B- acetates.

The above procedure is repeated using zinc dust in ethanol, with similarresults.

EXAMPLE 7 Sixty-two grams of zinc dust are shaken with 50 ml. of 3percent hydrogen chloride for 1 minute, washed three times with 50 ml.of 3 percent hydrogen chloride (decantation), and then abundantly withwater, twice with 100 ml. of 2 percent copper sulfate, abundantly withwater, three times with 95 percent ethanol, and four times with absoluteethanol. The washed zinccopper couple 1.5 g.) was added to a mixture of250 mg. of 1 7a-( 3-chloropropynyl l 7B-acetoxyestr-4-en- 3-one in 25ml. of absolute ethanol. The mixture is heated at reflux for 4 hoursafter which time it is filtered. Evaporation of solvent and purificationof the residue on silica gel G eluting with hexanezethyl acetate (7:3)gives l7a-propadienyll 7B-acetoxyestr-4-en-3- one which can be basehydrolyzed to the corresponding 1713-01.

EXAMPLE 8' A solution of 6,6-difluoro-l7a-(3-bromopropynyl)-l7B-acetoxyestr-4-en-3-one (2.8 g.) in anhydrous methanol (50 ml.) isheated with zinc-copper couple (18.7 g.) at 35 to 40C. with stirring.The progress of the reaction is continuously monitored by thin layerchromatography. When the formation of the desired product is essentiallycompleted, the reaction mixture is cooled, filtered, concentrated to ca.20 ml., diluted with water and product isolate isolated by extractionwith methylene dichloride. A solution of the resulting solid dissolvedin hexane:ether (2:1) is adsorbed on a column of silica gel. Elutionwith hexanezether (3:2) affords 6,6-difluorol 7a-propadienyl- 17fi-acetoxyestr 4- en-3-one. The product can be hydrolyzed or theprocedure performed with 6,6-difluoro-17a-(3bromopropynyl)-estr-4-en-l'7B-ol-3-one to give 6,6- difluorol7a-propadienylestr-4-enl 7B-0l-3-one.

The procedure of the present example is repeated with 6,6-difluoro- 17a-( 3-chloropropynyl )-l 7B-acetoxyestr-4-en-3-one and at 50 to 55C. togive 6,6- difluorol 7a-prop-adienyll 7B-acetoxyestr-4-en-3-one and,after hydrolysis, '6,6-difluoro-l7apropadienylestr-4-en-l7B-ol-3-one.This procedure is repeated using 6,6-difluoro-l7a-(3-chloropropynyl)-estr- 4-ene-3B,l7/3-diol as a starting compound to give6,6-difluoro-l7a-propadienylestr-4-en-3B,17B-di0l which is oxidized withmanganese dioxide, as described above to give6,6-difluoro-l7a-propadienylestr-4-enl7B-ol-3-one. Use of the313,17B-bistetrah'ydropyran- 2-yloxy starting compounds affords thecorresponding 33, 1 7/3-bistetrahydropyran-2-yloxyl 7a-propadienylproducts which can be hydrolyzed withmalonic acid, as described above,to give the diol followed by oxidation, as described above, .to give6,6-difluoro-.l7apropadienylestr-4-enl 7B-ol-3-one.

EXAMPLE 9 The reaction mixture of Preparation 15 containing 3,3-ethylenedioxy-6,6-difluoro- 1 7a-( 3) -chloropropynyl )-18-methylestr-4-en- 1 73-01 in anhydrous methanol (50 ml.) is heated withzinc-copper couple (18.7 'g.) at 50 to 55C. with stirring. The progressof the reaction is continuously monitored by thin layer chrom'atography.When the formation of the desired product is essentially completed, thereaction mixture is cooled, filtered, concentrated to ca. 20 ml.,diluted with water and the product isolated by extraction withmethylenedichloride. A solution of the resulting solid dissolved in The productcan be acetylated or the procedure performed with 6,6-difluoro- 1 7a-(3-chloropropynyl)- 1 7B- acetoxyestr-4-en-3-one to give6,6-difluoro-17apropadienyl-l 7B-acetoxyestr-4-en-3-one.

EXAMPLES 10 to 20 In accordance with the methods and procedures of thepresent invention, the following reactions are carried out.

By reacting together l7a-(3-fluoropropynyl)-17/3-acetoxy-l8-methylandrost-4-en-3-one and zinc dust with ethanol as liquidreaction medium and proton donor, in accordance with the method ofExample I, there is obtained the l7a-propadienyl-l 7B-acetoxy-l 8-methylandrost-4-en-3-one product.

By reacting together l7a-(3-chloropropynyl)-l8-ethylestr-4-en-l7B-ol-3-one and zinc-copper couple in ethanol andt-butanol medium in accordance with the method of Example 3, there isobtained the 17apropadienyl-l 8-ethylestr-4-enl 7/3-ol-3-one product.

By reacting together 17a-(3-bromopropynyl)-17B-propionyloxy-l8-n-propylestr-5(10)-en-3-one and aluminum metal intetrahydrofuran containing 10 percent t-butanol and heating to reflux inaccordance with the method of Example 3, there is obtained the17apropadienyll 7B-propionyloxy-l 8-n-propylestr-4'en-3- one product.

By reacting together l7d-(3-chloropropynyl)-l8-isopropylestra-l,3,5(l)-triene-3,l7B-diol and manganese metal in anisopropyl etherzisopropanol (9:1) medium in accordance with the methodof Example 3, there is obtained the correspondingl7a-propadienyll8-isopropylestral ,3 ,5( l0)-triene-3, l 7B-diolproduct.

By reacting together 3-ethoxy-l7a-(3-fluoropropynyl)-l7B-propionyloxyestra-l ,3,5( l0)-triene and zinc dust in propionic acidmedium at 50C. in accordance with the method of Example 1, there isobtained the 3- ethoxyl 7a-propadienyl- 1 7B-propionyloxy-l 8-methylestra-l ,3,5( 10).-triene product.

By reacting together l7a-(3-bromopropynyl )-17B-butyryloXy-l8-isopropylandrost-4-en-3-one and zinc dust in methanolmedium in accordance with the method of Example 1, there is obtained the17apropadienyll 7B-butyryloxy-l 8-isopropylandrost-4-en- 3-one product.

By reacting together 17a-(3-chloropropynyl)-l7B- acetoxy-l8-methylestr-4-en-3-one and chromium(0us) sulfate in aqueous acetonemedium under an atmosphere of nitrgoen in accordance with Example 4,there is obtained the corresponding l7a-propadienyll7B-acetoxy-18-methyIestr-4-en-3-one product.

By reacting together 3-methoxyl 7a-(3-fluoropropynyl)-l7B-tetrahydropyran-2-yloxyestral ,3,5( 10)- triene and chromous acetatein aqueous diethyl ketone and n-hexane in accordance with the method ofExample 4, there is obtained the corresponding 3-methoxyl7a-propadienyll 7B-tetrahydropyran-2'-yloxyestral,3,5(lO)-triene product.

By reacting together3B,]7/3-diacetoxy-6,6-difluorol7a-(3-chloropropynyl)androst-4-ene andchromous acetate in acetone and water in accordance with the method ofExample 4, there is obtained the 33,173-

diacetoxy-6,6-difluorol 7a-propadienylandrost-4-ene product.

In accordance with the foregoing methods, the following compounds areprepared, those methods employing an acid as liquid reaction medium orproton donor being avoided for the ether derivatives.

33,17B-bis(tetrahydropyran-2-yloxy)-6,6-difluorol7a-propadienylestr-4-ene,

6,6-difluorol 7a-propadienyl-l 7,8-acetoxyestr-4-en- 3-one.

6,6-difluorol 7a-propadienyll7B-propionyloxyandrost-4-en-3-one,

6,6-difluoro-17a-propadienyl-l7B-benzoyloxyestr-4- en-3-one,

6,6-difluorol 7a-propadieny-l-l 7B-adamantoyloxyestr-4-en-3-one,

3B-propionyloxy-6,6-difluoro- 1 7a-propadienylandrost-4-enl 73-01,

35, l 7,B-bis(adamantoyloxy )-6,6-difluoro-l 7apropadienylestr-4-ene,

3fl-(B-chloropropionyloxy)-6,6-difluoro- 1 7apropadienyll7B-tetrahydrofuran-2-yloxyandrost-4- ene,

3B-butyryloxy-6,6-difluorol 7 a-propadienyl- 1 7B-tetrahydropyran-2-yloxyandrost-4-ene,

3B-tetrahydropyran-2'-yloxy-6,6-difluoro-17apropadienyll7B-caproyloxyestr-4-ene,

3 B-tetrahydrofuran-Z'-yloxy-6,6-difluoro- 1 7apropadienyl- 17B-caproyloxyestr-4-ene,

3 ,B-tetrahydropyran-Z -yloxy-6,6-difluoro- 1 7apropadienyll7B-heptanoyloxyandrost-4-ene, and

331 7B-dipentanoyloxy-5 ,S-difluoro- 1 7apropadienylestr-4-ene.

Elaboration at C-3Bcan be performed after the principal reaction asfollows.

EXAMPLE 21 A solution of l g. of l7a-propadienylandrost-4-en-17,8-ol-3-one in 50 ml. of tetrahydrofuran is added over a 30 minuteperiod to a stirred suspension of l g. of lithium aluminum hydride in 50ml; of anhydrous tetrahydrofuran and this mixture is heated at refluxfor 2 hours. To the mixture are cautiously added 5 ml. of

ethyl acetate and 2 ml. of water. Sodium sulfate is nextadded, themixture isfiltered and the solid thus collected is washed with hot ethylacetate. The combined organic solutions are then evaporated to yield17apropadienylandrost-4-ene-3B,l7,8-diol which may be further purifiedthrough recrystallization from acetone:hexane.

In like manner, the other 3-0xo derivatives bearing a l7a-propadienylgrouping prepared in accordance herewith are reduced to thecorresponding 3,8-hydroxyl compounds, for example,

l7a-propadienylestr-4-ene-3B, l 7B-diol,

l 7a-propadienyll 7fl-tetrahydrofuran-2 -yloxyestr- 4-en-3B-ol, and

6,6-difluorol 7a-propadienylestrl-ene-3B, l 7B-diol.

EXAMPLE 22 A solution of l7a-propadienylestr-4-en-1713-01-3- one (0.35g.) and lithium tri-t-butoxyaluminum hydride (2.0 g.) in anhydroustetrahydrofuran (20 ml.) is heated under reflux for 16 hours, cooled anddiluted with water. The resultant mixture is extracted with severalportions of methylene dichloride and the combined extracts are washedwith water, dried (Na SO I one, 1 methylestr-4-en-3-one,l7a-propadienylestra-4,9(

and evaporated. Purification of the resultant product by preparative tlcaffords l7a-propadienylestr-4-en- 3B,]7B-diol.

Treatment of l7a-propadienylestr-4-en-3B, l 7/3-diol (0.20 g.) with 2.5ml. of acetic anhydride-pyridine (1:4) for 18 hours at room temperatureprovides the 3l3-acetoxyl 7a-propadienylestr-4-en- 1 78-01 product.

In like manner, from l7a-propadienyl-l8- methylestr-4-enl 7B-ol-3-one,6,6-difluoro-l 7apropadienylestr-4-en-l 7B-ol-3-one, 6,6-difluoro- 17apropadienyl-l 8-methylestr-4-enl 7B-ol-3-one,17apropadienyll7,8:acetoxyestr-4-en-3-one, 1 7apropadienyll 7B-acetoxyl8-methylestr-4-en-3-one,6,6-difluoro-l7a-propadienyl-17B-acetoxyestr-4-en-3-6,6-difluoro-l7a-propadienyl-l 7B-acetoxy-18- dienl 7B-ol-3-one,l7a-propadienylestra-5(10),9( l l dien-l 7/3-ol-3-one,l7a-propadienylestra-4,9( 10),! ltrien-17B-ol-3-one there isrespectively prepared:

3B-acetoxy-l7a-propadienyl-18-methylestr-4-en- 178-01,

6 ,6-difluoro-3B-acetoxy-1 7a-propadienylestr-4-en- 173-0],

6,6-difluoro-3B-acetoxyl 7a-propadienyll 8- methylestr-4-en- 1 713-01,3,13,17B-diacetoxy-l7apropadienylestr-4-en-3-one, 3B, 1 7B-diacetoxy-l7apropadienyl-l8-methylestr-4-en-3-one, 6,6-difluoro- 3B, 17fi-diacetoxy-l 7a-propadienylestr-4-en-3-one,6,6 -difluoro-3B, l7B-diacetoxyl 7a-propadienyll 8- methylestr-4-en-3-one, 3B-acetoxyl7a-propadienylestra-4,9( l0)-dienl 7B-ol, 3B-acetoxy- 17apropadienylestra-5(10),9(l 1 )-dien-1 78-01, and 3B- acetoxy-l7a-propadienyl-estra-4,9( l0),1 l-trien- I 7B- 0] through the 3B-hydroxycompounds.

EXAMPLE 23 One gram of l7a-propadienyl-l 7B-acetoxyestr-4-en- 3-one in50 ml. of tetrahydrofuran containing 3 grams of lithiumtri-t-butoxyaluminum hydride is heated under reflux for 45 minutes.'After this time, the solution is poured into water and extracted with 4X 250 ml. portions of ethyl acetate. The extracts are washed with water,dried and concentrated. The concentrate is chromatographed on 40 g. ofneutral aluminum to give l7a-propadienyll 7B-acetoxyestr-4-en-36-01which is crystallized from n-hexane.

EXAMPLE 24 Two milliliters of dihydropyran are added to a solution of lg. of l7a-propadienyl-l7B-caproyloxyandrost-4-en-3B-ol in IS ml. ofbenzene. About 1 ml. is removed by distillation to remove moisture and0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution.This mixture is allowed to stand at room temperature for 4 days, and isthen washed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield BB-tetrahydropyran-2'-yloxyl- 1 7apropadienyll7B-caproyloxyandrost-4-ene which is recrystallized from pentane.

To a solution of l g. of l7B-propadienylandrost-4- cane-3B,! 7/3-diol inm]. of benzene is added 20 ml. of dihydrofuran. Five milliliters isdistilled off to remove moisture, and the mixture is allowed to cool toroom temperature. To the cooled mixture, 0.2 g. of freshly purifiedp-toluenesulfonyl chloride is added. The mixture is stirred at roomtemperature for 24 hours and then poured into an excess of 5 percentaqueous bicarbonate solution. The product is extracted with ethylacetate, the organic solution is washed with water to neutral, diredover anhydrous magnesium sulfate, and evaporated to dryness underreduced pressure. The oily residue crystallizes on the addition of etherto yield the33,17B-bis(tetrahydrofuran-2-yloxy)-17ozpropadienylandrost-4-ene.

In like manner, the tetrahydropyranyl 1 and tetrahydrofuranyl ethers ofthe l7a-propadienyl compounds hereof are prepared, for example, 33-tetrahydropyran-2 '-yloxyl 7a-propadienyl-l 7B- acetoxy-l8-methylandrost-4-ene, 3 B-tetrahydrofuran- 2'-yloxy-l 7a-propadienyll7B-heptanoyloxyestr-5 lO)-ene,3,8,17B-bis(tetrahydropyran-2'-yloxy)-l701- propadienyll8-ethylandrost-4-ene, 3B-tetrahydropyran-2-yloxy-17a-propadienyl-l7B-adamantoyloxyl8-methylestr-4-ene, and bis(tetrahydropyran-2 -yloxy )-6,6-difluoro- 17a propadienyll 8-ethylandrost-4-ene.

EXAMPLE 25 A mixture of l g. ofl7a-propadienyl-l7B-acetoxyestr-4-en-3B-ol, 4 ml. of pyridine and 2 ml.of acetic anhydride is allowed to stand at room temperature for 15hours. The mixture is then poured into ice waterand the solid whichforms is collected by filtration, washed withwater and dried to yield3B,l7B-diacetoxy-l7apropadienylestr-4-ene which may be further purifiedthrough recrystallization from acetonezhexane.

Similarly, the corresponding 3B-esters of the other l7a-propadienylproducts thereof are prepared upon substitution of the appropriatestarting compund and conventional acylating. agent, for example, 33-trimethylacetoxy-l7a-propadienyl-17B-acetoxyestr-4- ene, 3fi, l7B-dipropionyloxy-l 7a-propadienylandrost-4 -ene,3B-butyryloxy-6,6-difluoro-l7a-propadienyl-17B-tetrahydropyran-Z'-yloxyestr-4-ene,3B-pentanoyloxy-l7a-propadienyl-17B-acetoxyestr-5( l0)- ene, 35,17B-bis(benzoyloxy)-l 7a-propadienylandrost- 4-ene, and3B-acetoxy-6,6-difluoro-l7a-propadienyll-7B-propionyloxyandrost-4-ene.

EXAMPLE 26 The corresponding C-3 substituted derivatives of thel7a-propadienyl products in the estrogen series are prepared inaccordance with the above procedures using the 3-hydroxyl derivative asstarting compund. This starting compound can be formed after theprincipal reaction hereof upon conventional hydrolysis of the protectivegrouping, such as a tetrahydropyran-2- yloxy grouping, with acidhydrolysis. Representative 3- substituted compounds of this series thusprepared are:

3-acetoxy-l 7a-propadienyll 7B-tetrahydropyran-2 yloxyestra-l ,3,5(lO)-triene,

3 l 7B-diacetoxyl 7a-propadienylestra-l ,3 ,5( l0 triene,

3 l 7B-bis( benzoyloxy l 7a-propadienyll 8-ethylestral ,3,5( l0)-triene,and

3-caproyloxyl 7a-propadienyll 7B-tetrahydrofuran- 2 -yloxyl8-propylestral ,3,5( l0)-triene. 7

Further representative 6,6-difluorol 7a-propadienylandrost-4-enes andl9-nor derivatives prepared in accordance with the above procedures areas follows:

l ethylandrost-4-ene,

33,17/3-dipropionyloxy-6,6-difluoro-l7apropadienylestr-4-ene,

33,17B-dipropionyloxy-6,6-difluoro-l7a-propadienyl-l8-methylandrost-4-ene,

38,17B-bis(tetrahydropyran-2'-yloxy)-6,6-difluorol8-isopropylestr-4-ene,

B, l 7,B-bis(tetrahydropyran-2 '-yloxy )-6,6-difluoroandrost-4-ene,

33,17B-bis(tetrahydrofuran-2 '-yloxy )-6,6-difluorol8-ethylandrost-4-ene,

313,17fi-bis(tetrahydrofuran-2 -yloxy )-6,6-dit'luorol8-ethylestr-4-ene,

6,6-difluorol 7a-propadienyll 7B-propionyloxyestr- 4-en-3-one, I

6,6-difluoro- 1 7a-propadienyl- 1 7B-propionyloxyl 8-methylestr-4-en-3-one,

6,6-difluoro-l7a-propadienyl-17,8-butyryloxyester- 4-en-3-one,

6,6-difluoro-17a-propadienyl-17B-butyryloxy-l 8- methyl-estr-4-en-3-one,

6,6-difluoro-17a-propadienyl-l7B-pentanoyloxyestr-4-en-3-one,

6,6-difluro-l 7a-pr0padienyl-17B-pentanoyloxy-l 8-methylestr-4-en-3-one,

6,6-diflu0ro-l 7a-propadienyll 7B-pentanoyloxyandrost-4-en-3-one,

6,6-difluorol 7a-propadienyl- 1 7B-hexanoyloxyestr- 4-en-3-one,

6,6-difluoro-17a-propadienyl-l7B-heptanoyloxyandrost-4-en-3-one,

6,6-difluorol 7a-propadienyll 7B-caproyl0xyestr-4- en-3 -one,

6,6-difluorol 7a-propadienyll 7B-caproyloxyl 8- methyl-estr-4-en-3-one,

6,6-difluoro- 1 7a-propadienyll 7B-benzoyloxyandrost-4-en-3-one,

6,6-difluorol 7a-propadienyll 7B-adamantoyloxyestr-4en-3-one,

6,6-difluoro-l 7a-propadienyll 7/3-(B-chloropropionyloxy)-estr-4-en-3-one,

6,6-difluoro-l7a-propadienyl-17B-trimethylacetoxyandrost-4-en-3-one,

6,6-difluoro-l 7a-propadienyl- 1 7B-trimethylacetox yestr-4-en-3-one.

What is claimed is:

propadienyl steriod.

2. The process according to claim I conducted at a temperature of fromabout C. to about 120C.

proton donor.

4. The process according to claim 1 wherein the re agent is a metalhaving an oxidation potential between 20 +2.37 to +0.74 volts inclusive.

5. The process according to claim 4 wherein the reagent is a metalselected from magnesium, aluminum,

and zinc.

ragent is zinc metal.

7. The process according to claim 6 conducted in a lower aliphaticalcohol or a carboxylic acid containing 9. The process according toclaim 8 wherein the reagent is chromous chloride.

10. The process according to claim 1 wherein the reagent is zinc-coppercouple.

11. The process according to claim 10 conducted in a lower aliphaticalcohol.

12. The process according to claim 1 wherein the l7a-(3-halopropynyl)steriod is a l7a-(3-chloropropy- 40 nyl) steroid.

13. The process according to claim 12 wherein the reagent is zinc metal.

14. The process according to claim 12 wherein the reagent is zinc-coppercouple.

mulas:

In on:

3. The process according to claim 2 conducted in organic liquid reactionmedium and in the presence of a 6. The process according to claim 5wherein the 1 wherein the re- 15. The process according to claimlwherein there is prepared a l7a-propadienyl steriod of one of theforpropadienylestr-4-ene methylestr-4-ene steriod is prepared.

l7a-propadienylestra-5( l),9(l l )-diene, propadienyl-estra-4,9(lO)-diene, propadienylestra-4,9( l0),l l-triene steriod is prepared.

the formula:

B on

R is hydrogen or lower alkyl of from 1 to 3 carbon atoms, inclusive; v

is hydrogen, tetrahydrofuran-Z-yl, l5

tetrahydropyran-Z-yl, or a carboxylic acyl group containing less than 12carbon atoms;

R is an oxo group or the group wherein,

17. The method claimed in claim 15 wherein a 6,6-

difluoro-l7a-propadienylestr-4-ene or a 6,6- difluoro- 17a-propadienyl-l8-methylestr-4-ene prepared.

steriod is 18. The process according to claim 15 wherein a 19. Acompound selected from those represented by 1 dlHz OR wherein R ishydrogen or lower alkyl of from 1 to 3 carbon atoms, inclusive;

R is 7 hydrogen,

tetrahydropyran-Z-yl, or a carboxylic acyl group containing less than 12carbon atoms;

R is an oxo group or the group in which R is hydrogen,tetrahydrofuranQ-yl, tetrahydropyran-Z-yl or a carboxylic acyl groupcontaining less than 12 carbon atoms; an R is hydorgen or methyl. 20.The compound according to claim 19 wherein R is hydrogen, R is hydrogen,R is an oxo group and R is hydrogen;6,6-difluoro-l7a-propadienylestr-4-enl7 -ol-3-one.

91. The compound according to claim 19 wherein R is hydrogen, R isacetyl, R is an oxo group and R is hydrogen; 6,6-difluorol7a-propadienyl-l 7B-acetoxyestr-4-en-3-one.

22. The compound according to claim 19 wherein R is methyl, R ishydrogen, R is an oxo group and R is hydrogen;6,6-difluoro-l7a-propadienyl-18- methylestr-4-en-l 7B-ol-3-one.

23. The compound according to claim 19 wherein R is methyl, R is acetyl,R is an oxo group and R is hydrogen; 6,6-difluorol 7a-propadienyl- 17B-acetoxy- 18-methylestr-4-en-3-one.

24. A compound selected from those of claim 19 of the formula:

wherein R is hydrogen or methyl and R is hydrogen or a carboxylic acylgroup containing less than 12 carbon atoms.

tetrahydrQfuran-Z-yl,

2. The process according to claim 1 conducted at a temperature of fromabout 20*C. to about 120*C.
 3. The process according to claim 2conducted in organic liquid reaction medium and in the presEnce of aproton donor.
 4. The process according to claim 1 wherein the reagent isa metal having an oxidation potential between +2.37 to +0.74 voltsinclusive.
 5. The process according to claim 4 wherein the reagent is ametal selected from magnesium, aluminum, and zinc.
 6. The processaccording to claim 5 wherein the ragent is zinc metal.
 7. The processaccording to claim 6 conducted in a lower aliphatic alcohol or acarboxylic acid containing less than 12 carbon atoms.
 8. The processaccording to claim 1 wherein the reagent is a chromium metal salt. 9.The process according to claim 8 wherein the reagent is chromouschloride.
 10. The process according to claim 1 wherein the reagent iszinc-copper couple.
 11. The process according to claim 10 conducted in alower aliphatic alcohol.
 12. The process according to claim 1 whereinthe 17 Alpha -(3-halopropynyl) steriod is a 17 Alpha -(3-chloropropynyl)steroid.
 13. The process according to claim 12 wherein the reagent iszinc metal.
 14. The process according to claim 12 wherein the reagent iszinc-copper couple.
 15. The process according to claim 1 wherein thereis prepared a 17 Alpha -propadienyl steriod of one of the formulas: 16.The method claimed in claim 15 wherein a 17 Alpha -propadienylestr-4-eneor a 17 Alpha -propadienyl-18-methylestr-4-ene steriod is prepared. 17.The method claimed in claim 15 wherein a 6,6-difluoro-17 Alpha-propadienylestr-4-ene or a 6,6-difluoro-17 Alpha-propadienyl-18-methylestr-4-ene steriod is prepared.
 18. The processaccording to claim 15 wherein a 17 Alpha-propadienylestra-5(10),9(11)-diene, 17 Alpha-propadienyl-estra-4,9(10)-diene, or 17 Alpha-propadienylestra-4,9(10),11-triene steriod is prepared.
 19. A compoundselected from those represented by the formula:
 20. The compoundaccording to claim 19 wherein R1 is hydrogen, R2 is hydrogen, R3 is anoxo group and R4 is hydrogen; 6,6-difluoro-17 Alpha-propadienylestr-4-en-17 Beta -ol-3-one.
 21. The compound according toclaim 19 wherein R1 is hydrogen, R2 is acetyl, R3 is an oxo group and R4is hydrogen; 6,6-difluoro-17 Alpha -propadienyl-17 Beta-acetoxyestr-4-en-3-one.
 22. The compound according to claim 19 whereinR1 is methyl, R2 is hydrogen, R3 is an oxo group and R4 is hydrogen;6,6-DIFLUORO-17 Alpha -propadienyl-18-methylestr-4-en-17 Beta -ol-3-one.23. The compound according to claim 19 wherein R1 is methyl, R2 isacetyl, R3 is an oxo group and R4 is hydrogen; 6,6-difluoro-17 Alpha-propadienyl-17 Beta -acetoxy-18-methylestr-4-en-3-one.
 24. A compoundselected from those of claim 19 of the formula: